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A forty-nine-year-old female from a suburban community in Sri Lanka presented with insidious high grade intermittent fever with chills and rigors for 2 months. She experienced one to two febrile episodes daily with complete defervescence in between. She also had anorexia, weight loss, sore-throat and symmetrical large joint arthritis without morning stiffness. Small joints and axial skeleton were spared. She also noticed an itchy desquamating erythematous rash over back of the trunk and proximal limbs. Erythematous patches were transient and recurring but did not temporally correspond to febrile peaks. The patient did not have any symptoms referable to a focus of infection and did not report photosensitivity, Raynaud phenomenon, past history of tuberculosis, or high risk sexual behaviours.\nThe patient was averagely built (BMI: 23.1 kg/m2), febrile (39.9 °C), ill and pale. A firm 1.5 cm lymph node in the right posterior cervical group was noted. Throat was non-inflamed. Erythematous macules noted over the trunk and proximal limbs were transient. Symmetric arthritis affected elbow, wrist and knee joints. A smooth non-tender 2 cm hepatomegaly was noted. The rest of the examination was unremarkable.\nInvestigations revealed a normocytic normochromic anaemia, neutrophil leukocytosis with toxic changes, reactive thrombocytosis, elevated ESR (110 mm 1st hour), CRP (165 U/L) and ferritin (3200 U/L). Renal function was normal and liver enzymes were mildly elevated (AST 66 U/L, ALT 57 U/L). Auto antibody panel, including rheumatoid factor, antinuclear antibodies (ANA), dsDNA antibodies, pANCA and cANCA were negative. Contrast enhanced computerized tomography of the neck, chest, abdomen and pelvis demonstrated enlarged cervical lymph nodes and fatty liver. Radiographs of large joints were normal. Biopsy of the lymph node showed reactive lymphoid hyperplasia with no evidence of neoplastic changes, suppuration or granuloma. Bone marrow aspiration and trephine showed no abnormalities. Blood and bone marrow cultures for bacteria, tuberculosis, brucellosis, melioidosis and fungi were negative. Serum protein electrophoresis showed polyclonal gamma-globulinaemia and reduced albumin fraction. As she had been exposed to flood water 2 weeks prior to symptom onset (compatible with incubation period of 1–3 weeks) and several cases of melioidosis had been reported in her residential area, antibodies against Burkholderia pseudomallei were tested. It turned positive (1:640, indirect haemagglutination) and titre continued to rise over time (Fig. ).\nFebrile illness, possible exposure to infectious agents during floods and elevated inflammatory markers necessitated consideration of empiric antibiotic therapy. The patient was treated with ceftazidime (2 g 6 hourly IV) and imipenem (1 g 8 hourly IV) for 14 days and ceftazidime and cotrimoxazole (1440 mg bid orally) for another 14 days, due to positive serology for melioidosis. However she did not show clinical improvement. Fever persisted and inflammatory markers remained elevated. Serum ferritin and melioidosis antibody titre continued to rise exponentially. However repeated peripheral blood cultures for melioidosis did not isolate any bacteria and repeated imaging did not reveal a focus of infection.\nDespite a month of broad spectrum antibiotics she remained febrile with persistently elevated inflammatory markers. In retrospect, AOSD was considered as a possible diagnosis. She showed partial response to NSAIDs, further favouring this diagnosis. Subsequently, she was commenced on high dose steroids (prednisolone 1 mg/kg/day). Within 2 days she achieved complete defervescence and made a good clinical recovery. Serum ferritin level and melioidosis antibody titre declined over time (Fig. ). After one month of steroid therapy she remained afebrile, but had mild residual large joint arthritis with minimal functional impairment. Methotrexate was commenced and steroids were tapered over next 2 months and at 6 months she remained asymptomatic on methotrexate with normal inflammatory markers. Long term follow up was arranged.\nThe final diagnosis of AOSD was made based on clinical features and exclusion of other connective tissue disorders, neoplasms and infections. During the course of her illness the patient did not develop Macrophage Activation Syndrome, a serious complication of AOSD.

A 32-year-old male with a history of B. cenocepacia and Burkholderia multivorans developed an erythematous rash on the lower legs associated with an infective exacerbation of his chest. The rash resolved leaving grey discolouration but would occasionally flare up in the summer months. The biopsy showed features of capillaritis, and he was managed with topical steroids and compression hosiery.

Write a detailed clinical case vignette based on the following key phrases: Infectious diseases, Bacterial infections, Rare diseases

A forty-nine-year-old female from a suburban community in Sri Lanka presented with insidious high grade intermittent fever with chills and rigors for 2 months. She experienced one to two febrile episodes daily with complete defervescence in between. She also had anorexia, weight loss, sore-throat and symmetrical large joint arthritis without morning stiffness. Small joints and axial skeleton were spared. She also noticed an itchy desquamating erythematous rash over back of the trunk and proximal limbs. Erythematous patches were transient and recurring but did not temporally correspond to febrile peaks. The patient did not have any symptoms referable to a focus of infection and did not report photosensitivity, Raynaud phenomenon, past history of tuberculosis, or high risk sexual behaviours.\nThe patient was averagely built (BMI: 23.1 kg/m2), febrile (39.9 °C), ill and pale. A firm 1.5 cm lymph node in the right posterior cervical group was noted. Throat was non-inflamed. Erythematous macules noted over the trunk and proximal limbs were transient. Symmetric arthritis affected elbow, wrist and knee joints. A smooth non-tender 2 cm hepatomegaly was noted. The rest of the examination was unremarkable.\nInvestigations revealed a normocytic normochromic anaemia, neutrophil leukocytosis with toxic changes, reactive thrombocytosis, elevated ESR (110 mm 1st hour), CRP (165 U/L) and ferritin (3200 U/L). Renal function was normal and liver enzymes were mildly elevated (AST 66 U/L, ALT 57 U/L). Auto antibody panel, including rheumatoid factor, antinuclear antibodies (ANA), dsDNA antibodies, pANCA and cANCA were negative. Contrast enhanced computerized tomography of the neck, chest, abdomen and pelvis demonstrated enlarged cervical lymph nodes and fatty liver. Radiographs of large joints were normal. Biopsy of the lymph node showed reactive lymphoid hyperplasia with no evidence of neoplastic changes, suppuration or granuloma. Bone marrow aspiration and trephine showed no abnormalities. Blood and bone marrow cultures for bacteria, tuberculosis, brucellosis, melioidosis and fungi were negative. Serum protein electrophoresis showed polyclonal gamma-globulinaemia and reduced albumin fraction. As she had been exposed to flood water 2 weeks prior to symptom onset (compatible with incubation period of 1–3 weeks) and several cases of melioidosis had been reported in her residential area, antibodies against Burkholderia pseudomallei were tested. It turned positive (1:640, indirect haemagglutination) and titre continued to rise over time (Fig. ).\nFebrile illness, possible exposure to infectious agents during floods and elevated inflammatory markers necessitated consideration of empiric antibiotic therapy. The patient was treated with ceftazidime (2 g 6 hourly IV) and imipenem (1 g 8 hourly IV) for 14 days and ceftazidime and cotrimoxazole (1440 mg bid orally) for another 14 days, due to positive serology for melioidosis. However she did not show clinical improvement. Fever persisted and inflammatory markers remained elevated. Serum ferritin and melioidosis antibody titre continued to rise exponentially. However repeated peripheral blood cultures for melioidosis did not isolate any bacteria and repeated imaging did not reveal a focus of infection.\nDespite a month of broad spectrum antibiotics she remained febrile with persistently elevated inflammatory markers. In retrospect, AOSD was considered as a possible diagnosis. She showed partial response to NSAIDs, further favouring this diagnosis. Subsequently, she was commenced on high dose steroids (prednisolone 1 mg/kg/day). Within 2 days she achieved complete defervescence and made a good clinical recovery. Serum ferritin level and melioidosis antibody titre declined over time (Fig. ). After one month of steroid therapy she remained afebrile, but had mild residual large joint arthritis with minimal functional impairment. Methotrexate was commenced and steroids were tapered over next 2 months and at 6 months she remained asymptomatic on methotrexate with normal inflammatory markers. Long term follow up was arranged.\nThe final diagnosis of AOSD was made based on clinical features and exclusion of other connective tissue disorders, neoplasms and infections. During the course of her illness the patient did not develop Macrophage Activation Syndrome, a serious complication of AOSD.

A 23-year-old female with B. cenocepacia developed an erythematous maculopapular rash on the lower legs with associated arthropathy of her finger joints. This was clinically felt to be reactive leucocytoclastic vaculitis and a biopsy was not conducted. The vasculitis did not respond initially to oral prednisolone, and she was then commenced on azathioprine and the rash responded to this. Two years later, she died following a severe infective exacerbation of her chest.

Write a detailed clinical case vignette based on the following key phrases: Infectious diseases, Bacterial infections, Rare diseases

A forty-nine-year-old female from a suburban community in Sri Lanka presented with insidious high grade intermittent fever with chills and rigors for 2 months. She experienced one to two febrile episodes daily with complete defervescence in between. She also had anorexia, weight loss, sore-throat and symmetrical large joint arthritis without morning stiffness. Small joints and axial skeleton were spared. She also noticed an itchy desquamating erythematous rash over back of the trunk and proximal limbs. Erythematous patches were transient and recurring but did not temporally correspond to febrile peaks. The patient did not have any symptoms referable to a focus of infection and did not report photosensitivity, Raynaud phenomenon, past history of tuberculosis, or high risk sexual behaviours.\nThe patient was averagely built (BMI: 23.1 kg/m2), febrile (39.9 °C), ill and pale. A firm 1.5 cm lymph node in the right posterior cervical group was noted. Throat was non-inflamed. Erythematous macules noted over the trunk and proximal limbs were transient. Symmetric arthritis affected elbow, wrist and knee joints. A smooth non-tender 2 cm hepatomegaly was noted. The rest of the examination was unremarkable.\nInvestigations revealed a normocytic normochromic anaemia, neutrophil leukocytosis with toxic changes, reactive thrombocytosis, elevated ESR (110 mm 1st hour), CRP (165 U/L) and ferritin (3200 U/L). Renal function was normal and liver enzymes were mildly elevated (AST 66 U/L, ALT 57 U/L). Auto antibody panel, including rheumatoid factor, antinuclear antibodies (ANA), dsDNA antibodies, pANCA and cANCA were negative. Contrast enhanced computerized tomography of the neck, chest, abdomen and pelvis demonstrated enlarged cervical lymph nodes and fatty liver. Radiographs of large joints were normal. Biopsy of the lymph node showed reactive lymphoid hyperplasia with no evidence of neoplastic changes, suppuration or granuloma. Bone marrow aspiration and trephine showed no abnormalities. Blood and bone marrow cultures for bacteria, tuberculosis, brucellosis, melioidosis and fungi were negative. Serum protein electrophoresis showed polyclonal gamma-globulinaemia and reduced albumin fraction. As she had been exposed to flood water 2 weeks prior to symptom onset (compatible with incubation period of 1–3 weeks) and several cases of melioidosis had been reported in her residential area, antibodies against Burkholderia pseudomallei were tested. It turned positive (1:640, indirect haemagglutination) and titre continued to rise over time (Fig. ).\nFebrile illness, possible exposure to infectious agents during floods and elevated inflammatory markers necessitated consideration of empiric antibiotic therapy. The patient was treated with ceftazidime (2 g 6 hourly IV) and imipenem (1 g 8 hourly IV) for 14 days and ceftazidime and cotrimoxazole (1440 mg bid orally) for another 14 days, due to positive serology for melioidosis. However she did not show clinical improvement. Fever persisted and inflammatory markers remained elevated. Serum ferritin and melioidosis antibody titre continued to rise exponentially. However repeated peripheral blood cultures for melioidosis did not isolate any bacteria and repeated imaging did not reveal a focus of infection.\nDespite a month of broad spectrum antibiotics she remained febrile with persistently elevated inflammatory markers. In retrospect, AOSD was considered as a possible diagnosis. She showed partial response to NSAIDs, further favouring this diagnosis. Subsequently, she was commenced on high dose steroids (prednisolone 1 mg/kg/day). Within 2 days she achieved complete defervescence and made a good clinical recovery. Serum ferritin level and melioidosis antibody titre declined over time (Fig. ). After one month of steroid therapy she remained afebrile, but had mild residual large joint arthritis with minimal functional impairment. Methotrexate was commenced and steroids were tapered over next 2 months and at 6 months she remained asymptomatic on methotrexate with normal inflammatory markers. Long term follow up was arranged.\nThe final diagnosis of AOSD was made based on clinical features and exclusion of other connective tissue disorders, neoplasms and infections. During the course of her illness the patient did not develop Macrophage Activation Syndrome, a serious complication of AOSD.

A 42 year old diabetic woman from North Western Province of Sri Lanka presented with abdominal pain, vomiting and intermittent fever for one month. She had recurrent skin abscesses 6 months before presentation which was treated with incision and drainage and a short course of antibiotics for which there was only partial improvement. Three months before presentation to us she was found to have multiple liver abscesses which were aspirated in a local hospital. The aspirate grew “coliforms” resistant to gentamicin and sensitive to ceftazidime. She was treated with cefuroxime, meropenem, co-amoxyclav and metronidazole; further identification of the organism was not done at the local hospital.\nOn presentation to us she had high fever and tender hepatomegaly. Her body weight was 40 kg. Rest of the examination including nervous system was normal.\nHer full blood count showed leukocytosis [15.7×109/L] and granulocytosis [11.3 × 109/L], ESR was 100 mm in the 1st hour and C-reactive protein was 98.4 mg/L. Ultra sound scan of abdomen showed multiple liver and splenic abscesses.\nPresence of recurrent multiple liver and splenic abscesses in a diabetic patient who had recurrent skin abscess in the past made us consider melioidosis in the differential diagnosis. Intravenous meropenem 2g eight hourly was started empirically and aspirate was sent with a sample of serum to Faculty of Medicine, University of Colombo which serves as the National Reference Laboratory, to confirm the diagnosis. There the aspirate yielded pinpoint colonies on blood, chocolate and Macconkey agar after overnight incubation. Since biochemical panels are not very accurate in diagnosis of Burkholderia pseudomallei, isolate was subjected to PCR which confirmed the diagnosis.\nSerum antibodies to melioidin antigen using an in-house indirect haemagglutination (IHA) test based on that described by Alexander et al. with antigen prepared from local strains of B.pseudomallei [] were positive at a titre of 1:10240.\nAfter confirmation of melioidosis intravenous meropenem was continued. However after a week of treatment the disease course was complicated by bilateral lower limb weakness which progressed over the next 4 days. Her lower limbs were flaccid and deep tendon reflexes were absent. There was no sensory sign or bladder/bowel involvement. Cerebro-spinal fluid analysis showed protein of 114.5 mg/dl, glucose 62 mg/dl, white cells <10 mm9/L and red cells < 10 mm9/L. MRI scan of the brain was normal. The nerve conduction study showed evidence of severe peripheral neuropathy with axonal degeneration; compatible with a primary axonal type inflammatory neuropathy such as acute motor axonal neuropathy or acute sensory motor axonal neuropathy.\nA diagnosis of Guillan-Barre syndrome was made based on Brighton case definition (Table ) () and she was treated with 4 cycles of plasmapharesis on alternate days for which there was marked improvement of neurological deficit.\nWith intravenous meropenem patient further improved and her ESR and CRP became normal. Repeat ultrasound scan of abdomen showed reduction of the size of liver and splenic abscesses.\nEradication therapy with cotrimoxazole 1920 mg 12 hourly and co-amoxyclav 625 mg 8 hourly was started on the seventh week and overlapped with intravenous antibiotic for further two weeks. Patient was discharged to outpatient clinic after two weeks of oral antibiotics with a plan to continue them for12 weeks. At the end of 12 weeks she had no residual neurological weakness and there was no sign of a relapse.

Write a detailed clinical case vignette based on the following key phrases: Infectious diseases, Bacterial infections, Rare diseases

We present the case of a 15-year-old female heterozygous for ΔF508del/N1303K, with poorly controlled lung disease determined by forced expiratory volume in one second (FEV1) 44% of predicted value, who presented with cutaneous vasculitis and arthritis in association with an infective exacerbation of CF. The cutaneous involvement consisted of a palpable purpuric rash distributed over the tibial surfaces, ankles, and dorsa of the feet (Figure ). At this admission in 2015, infection and colonization with BCC and methicillin-resistant Staphylococcus aureus (MRSA) later in the year were also diagnosed. Blood work at admission is presented in Table ; acute phase reactants (C-reactive protein and fibrinogen) and rheumatoid factor were elevated. ANCAs were negative. Antinuclear antibodies (ANAs) were negative initially, but became positive five years later. Over the next several years, the patient required on average three to four hospitalizations every year due to IECF. Cutaneous vasculitis was present in approximately every other episode of IECF and improved with treatment of the pulmonary exacerbations. Bacterial colonization together with respiratory function is summarized in Figure - of note, the FEV1 decreased from 65% at 14 years of age (before appearance of the vasculitis) to 24% by 19 years of age.\nFrom the patient’s medical history, we consider eloquent the following facts: at the age of two years, she received nine-month isoniazid prophylaxis due to contact with her father who had tuberculosis. At the age of three years, she was diagnosed with bronchiectasis via CT. At the age of nine years, colonization with Pseudomonas aeruginosa was diagnosed through bronchoalveolar lavage and she had an FEV1 of 75% predicted. At the age of 13 years, the patient was diagnosed with a latent pulmonary tuberculosis infection which was again treated with nine months of isoniazid monotherapy. At the age of 14 years, she was diagnosed with allergic bronchopulmonary aspergillosis, via elevated total IgE and Aspergillus-specific IgE. At this time, the patient had an FEV1 of 65% predicted.\nAt the age of 15 years (2015), colonization with BCC was noted, she had an FEV1 of 44% predicted. At this time, the patient showed first signs of the cutaneous vasculitis, in form of a palpable purpuric, nonvesicular maculopapular rash localized to the lower legs. The lower extremities were slightly swollen, painful, and as the episodes of the vasculitis continued to erupt, grey discoloration in the place of the rash began to set in and over the years became permanent. At the age of 18 years (2018), colonization with Achromobacter xylosoxidans and Candida parapsilosis was noted, she had an FEV1 of 24% during the exacerbation, which improved to 38% of predicted after treatment. The chest x-ray comparison from 2015 to 2017 is presented in Figure and B, respectively. The CT scan done at this time showed cystic dilations in the right apex (Figure ) and severe bilateral middle lung field cylindrical bronchiectasis with signet-ring signs (Figure ).\nTreatment was started with long-term oral prednisone. Colonization with Pseudomonas, BCC, MRSA, Achromobacter xylosoxidans, and Candida parapsilosis was treated with multiple courses of inhaled, IV and oral antibiotics (linezolid, ceftazidime, ofloxacin) and antifungals (fluconazole and voriconasole). In addition, the following was administered: azithromycin (three days a week for three months), tiotropium, an antihistamine, and periodic cough assist with antibiotic aerosol treatment. Starting from 2019, the patient’s nebulization with colistin and tobramycin was supplemented with nightly positive-pressure ventilation (PPV), but the ventilation was discontinued six months later due to slight hemoptysis that was predominantly present in the morning. Throughout the six months, the patient was on PPV, she experienced twp IECF, which required hospitalization. The two episodes of IECF, together with the extensive bronchiectasis, may have contributed to the appearance of the hemoptysis, which may have predisposed certain areas of the lung to barotrauma. After the PPV was discontinued, the hemoptysis disappeared and did not require any more treatment.

A 26-year-old female with B. cenocepecia presented with a history of recurrent small joint pains in association with intermittent painful erythematous nodular rash on the lower legs. This came on at the onset of an infective exacerbation of her chest. Biopsy confirmed erythema nodosum. Other causes of erythema nodosum were excluded, and she did not respond to Non-steroidal anti-inflammatory medications. Her symptoms continue to relapse in association with infective exacerbations of her chest.\nOf the remaining patients (n = 3), one presented with an erythematous rash on the lower legs and another had a purpuric rash on the lower legs and both were diagnosed clinically as leucocytoclastic vasculitis by a dermatologist. The third patient presented with purpuric areas and blistering of the lower legs which was confirmed as leucocytoclastic vasculitis on biopsy.\nOverall, two patients had biopsy proven leucocytoclastic vasculitis, three were clinically diagnosed with vasculitis but did not have biopsy confirmation and two had biopsies, which revealed other pathologies (erythema nodosum and capillaritis), giving an overall prevalence of cutaneous vasculitis in patients with Burkholderia cepacia complex of 16.7%. Out of the five patients with vasculitis, three had a raised ESR/CRP ratio.\nThere was no evidence of renal involvement in any patient – all had a negative urine dipstick and normal serum creatinine. The antinuclear antibody and antineutrophil cytoplasmic antibody were negative in all patients apart from one with biopsy proven leucocytoclastic vasculitis who had a transiently positive antineutrophil cytoplasmic antibody. Antistreptolysin O titre was tested in only two out of the five patients and was negative.\nMean forced expiratory volume1 was 30% (range: 18–55) of the predicted value. In four patients (57%), the forced expiratory volume1 was lower at the time of presentation with rash compared to the baseline forced expiratory volume1 values for the previous two years.\nAll patients received antibiotics for a presumed pulmonary exacerbation at onset of the rash. Three patients received specific treatment for vasculitis (prednisolone ± additional immunosuppressive) after non-resolution of the rash.

Write a detailed clinical case vignette based on the following key phrases: Infectious diseases, Bacterial infections, Rare diseases

A 42-year-old Sri Lankan man presented to the Colombo North Teaching Hospital, Ragama, Sri Lanka (CNTH) with a febrile illness of 6 days, accompanied by headache and constitutional symptoms. He was a grocer from Minuwangoda, a suburban area in the Western Province situated 44 km from Colombo. He was initially investigated and treated at a regional hospital for 4 days, and was transferred to the CNTH for specialized care. He gave a history of type 2 diabetes mellitus for 5 years without microvascular or macrovascular complications, and was a nonsmoker and a teetotaler. There were no specific symptoms suggesting a source of infection such as cough, abdominal pain, urinary symptoms, etc. He was febrile with a temperature of 39.10 C, and examination of the heart, lungs and abdomen was unremarkable. There was no papilloedema, focal neurological signs, pyramidal signs or neck stiffness. Initial laboratory work up revealed features of a bacterial infection, with neutrophil leukocytosis and elevated inflammatory markers (erythrocyte sedimentation rate – 101 mm/1st hour, C-reactive protein - 220 mg/dl). Initial blood cultures done at the regional hospital had yielded an isolate, which was reported as a Pseudomonas species; this was sensitive to ceftazidime, imipenem and meropenem and resistant to gentamicin and ceftriaxone. Other basic laboratory investigations including renal and liver function tests, electrolyte panel and urinalysis were normal. Chest x-ray and ultrasound scan of the abdomen were normal, and the trans-thoracic 2-D echo did not show any vegetations. As the unusual antibiotic sensitivity pattern suggested the possibility of melioidosis, blood was sent for serological testing to a specialized Melioidosis Research Laboratory at the Faculty of Medicine, University of Colombo.\nHe had been initially treated with intravenous ceftriaxone, and later with ceftazidime according to the antibiotic sensitivity pattern. Although the frequency and intensity of fever spikes reduced with treatment, he continued to have low grade fever and complain of anorexia, malaise and lethargy. On the 4th day after admission to the CNTH (day 10 of the illness), he developed simple partial seizures involving the left lower limb, progressing to persistent numbness of the left side of the body. An urgent CT scan of the head revealed a subdural collection over the right fronto-parietal region with gas locules and obliteration of sulci and gyri, without definite evidence of abscess formation (Fig. ). Contrast enhanced MRI scan of the brain demonstrated a subdural collection in the right fronto-temporo-parietal region with possible abscess formation in the right parietal region (Fig. ). Seizures were treated with oral sodium valproate and phenytoin sodium. He was referred for neurosurgical opinion, and the subdural collection was managed conservatively. Results of the indirect hemagglutination assay (IHA) for melioidosis antibodies were received on the following day; an antibody titre of more than 1/10,240 was strongly suggestive of an acute infection with Burkhoderia pseudomallei and a diagnosis of cerebral melioidosis was made.\nAntibiotics were changed to intravenous meropenem and oral trimethoprim/sulfamethoxazole (Co-trimoxazole/TMP-SMX). Initial intensive therapy with these antibiotics was continued for 8 weeks, until clinical improvement was evident with resolution of inflammatory markers and radiological improvement confirmed by repeat MRI scan of the brain. (Fig. ) Repeat blood cultures were sterile after 2 weeks of treatment with antibiotics. There were no further seizures, and the fever and the neurological symptoms resolved completely. He was discharged home with oral TMP-SMX and doxycycline, which were continued for 6 months, and the antiepileptics were gradually tailed off. At 6 months follow up he was asymptomatic. (Fig. ).

A 26-year-old female with B. cenocepecia presented with a history of recurrent small joint pains in association with intermittent painful erythematous nodular rash on the lower legs. This came on at the onset of an infective exacerbation of her chest. Biopsy confirmed erythema nodosum. Other causes of erythema nodosum were excluded, and she did not respond to Non-steroidal anti-inflammatory medications. Her symptoms continue to relapse in association with infective exacerbations of her chest.\nOf the remaining patients (n = 3), one presented with an erythematous rash on the lower legs and another had a purpuric rash on the lower legs and both were diagnosed clinically as leucocytoclastic vasculitis by a dermatologist. The third patient presented with purpuric areas and blistering of the lower legs which was confirmed as leucocytoclastic vasculitis on biopsy.\nOverall, two patients had biopsy proven leucocytoclastic vasculitis, three were clinically diagnosed with vasculitis but did not have biopsy confirmation and two had biopsies, which revealed other pathologies (erythema nodosum and capillaritis), giving an overall prevalence of cutaneous vasculitis in patients with Burkholderia cepacia complex of 16.7%. Out of the five patients with vasculitis, three had a raised ESR/CRP ratio.\nThere was no evidence of renal involvement in any patient – all had a negative urine dipstick and normal serum creatinine. The antinuclear antibody and antineutrophil cytoplasmic antibody were negative in all patients apart from one with biopsy proven leucocytoclastic vasculitis who had a transiently positive antineutrophil cytoplasmic antibody. Antistreptolysin O titre was tested in only two out of the five patients and was negative.\nMean forced expiratory volume1 was 30% (range: 18–55) of the predicted value. In four patients (57%), the forced expiratory volume1 was lower at the time of presentation with rash compared to the baseline forced expiratory volume1 values for the previous two years.\nAll patients received antibiotics for a presumed pulmonary exacerbation at onset of the rash. Three patients received specific treatment for vasculitis (prednisolone ± additional immunosuppressive) after non-resolution of the rash.

Write a detailed clinical case vignette based on the following key phrases: Infectious diseases, Bacterial infections, Rare diseases

In February 2006, a previously healthy 58-year-old Sinhalese woman presented to our hospital with a history of intermittent fever, headache, loss of appetite, loss of weight, dry cough, and arthralgia of 5 weeks’ duration. She had no known past medical conditions or any family history of chronic disorders or similar illnesses. She was a housewife who frequently engaged in gardening and had no history of visits to forest areas or working in paddy fields. She was not alcoholic and was a nonsmoker.\nAt the beginning, she had been hospitalized, had undergone investigations, and had received broad-spectrum antibiotics. Due to the nature of the protracted illness with fever, and because she had an erythrocyte sedimentation rate (ESR) above 100 mm/h and increased C-reactive protein (CRP), a course of antituberculous antibiotics had been given over 2 weeks without definitive confirmation of the diagnosis of tuberculosis. While on antituberculous medications, instead of clinical improvement, she showed further deterioration of her illness and developed new problems, including appearance of a tender lump over the right temporal area over the course of 1 week and another similar lump over the anterior aspect of the left thigh of 5 days’ duration. At this juncture, she left the first hospital at her own wish and secured admission to Teaching Hospital Peradeniya (THP).\nOn admission to THP, she looked very ill and feeble and was febrile and tachypneic. She had a tender lump resembling an abscess over the right temporal area. Furthermore, she had similar lumps over the anterior aspect of the left thigh. She had an inflamed, swollen knee and wrist joints with a tender erythematous rash over both shins that resembled erythema nodosum. Her pulse rate was 110 beats/min with blood pressure of 100/65 mmHg. The results of her respiratory system and abdominal examinations were clinically normal. She was conscious, rational, and had no neck stiffness, with a clinically normal neurological examination result.\nBlood samples were taken for basic investigations and culture at this juncture. Diagnostic needle aspirates from the cystic lumps and knee joint effusions were purulent and were sent for bacteriological investigations. Blood samples for cultures were taken under aseptic conditions. Three separate blood cultures were taken in 30-minutes intervals and drawn into standard blood culture bottles. Knee joint and skin lump aspirates also were drawn into separate culture bottles under aseptic conditions. All the samples were transported to the microbiology laboratory, which is located within the hospital premises, and the cultures were done by a consultant microbiologist. Pending investigations, the patient was treated with intravenous (IV) co-amoxiclav (amoxicillin mixed with clavulanic acid).\nOn the fifth day of the patient’s admission, she became drowsy and developed focal seizures involving the right upper and lower limbs and lasting for around 2 minutes. She became drowsy with a Glasgow Coma Scale (GCS) score of 12/15. She moved all her limbs, and her deep tendon reflexes were normal, but she had an upgoing plantar response. She had no neck stiffness, positive Kernig sign, or focal neurological signs. She had persistent tachycardia with low blood pressure of 90/50 mmHg. Her respiratory rate was 30 breaths/min, and she had bibasal crepitations. She had bilateral knee joint effusions, and her knee joints were swollen, warm, erythematous, and tender. A tentative diagnosis of cerebral abscesses was made, and the patient was transferred to the intensive care unit.\nUrgent contrast-enhanced computed tomography of the brain showed a well-defined cystic mass in the right temporal region outside the skull vault and contrast-enhanced changes in the adjacent brain matter. Furthermore, a 12-lead electroencephalogram (EEG) showed a theta-wave focus over the right temporal area with intermittent epileptiform discharges compatible with structural brain damage. The results of her ultrasound examination of the abdomen and an echocardiogram were normal. Her white blood cell count was 3.3 × 109/L with neutrophils of 83% and lymphocytes of 12%. Her ESR was 120 mm/first hour, and her CRP level was 192 mg/L. Her chest x-ray showed multiple peripherally located, ill-defined cystic areas in both lung fields, more in the lung bases, suggestive of multiple lung abscesses. By that time, the blood culture, knee joint aspirate, and skin lump aspirates grew B. pseudomallei, which was confirmed by the local microbiologists with the help of international reference laboratories []. Thus, a diagnosis of melioidosis was confirmed, and treatment commenced.\nFollowing the confirmed diagnosis her antibiotic regimen was changed and started on IV meropenem 1 g 8-hourly for 8 days and later changed to IV imipenem 500 mg 6-hourly, based on the antibiotic sensitivity pattern of the bacterial isolate. Two more antibiotics were added to the regimen at the same time: IV ciprofloxacin 400 mg 12-hourly and IV ceftazidime 2 g 6-hourly. The patient showed gradual improvement of her general condition, and her fever subsided in a few days. However, all three antibiotics were continued for 30 days and changed to an oral antibiotic course comprising cotrimoxazole 1920 mg twice daily plus doxycycline 100 mg twice daily for 20 more weeks. Her seizures were controlled with sodium valproate 200 mg thrice daily. In follow-up, the patient’s chest x-ray, ESR (50 mm/h), CRP (0.7 mg/dl), and liver and renal profiles showed gradual improvement, and the results of her retroviral screening were negative. Her blood sugar and hemoglobin A1c levels were within normal limits. The result of repeat EEG in 3 months’ time was normal, and the patient’s sodium valproate was gradually tapered. After 6 months of antibiotic treatment, her ESR was 12 mm/first hour; her CRP was < 6 mg/L; and all of her other biochemical parameters were normal. Then, she was advised to come back to our hospital for annual screening to check for recurrence of the disease, including ESR and CRP measurement. She has had no recurrence of her illness during the last 13 years and remains well.\nSubsequently, how she contracted the infection was inquired about. She was able to recall contact with soil a few days prior to developing her illness. The footpath leading to her home had a side drain that was filled with mud and soil. She found that a worker had dug up the drain and piled mud and soil on the footpath. The patient, dismantled the piled-up soil with her bare feet and made the footpath accessible.

A 26-year-old female with B. cenocepecia presented with a history of recurrent small joint pains in association with intermittent painful erythematous nodular rash on the lower legs. This came on at the onset of an infective exacerbation of her chest. Biopsy confirmed erythema nodosum. Other causes of erythema nodosum were excluded, and she did not respond to Non-steroidal anti-inflammatory medications. Her symptoms continue to relapse in association with infective exacerbations of her chest.\nOf the remaining patients (n = 3), one presented with an erythematous rash on the lower legs and another had a purpuric rash on the lower legs and both were diagnosed clinically as leucocytoclastic vasculitis by a dermatologist. The third patient presented with purpuric areas and blistering of the lower legs which was confirmed as leucocytoclastic vasculitis on biopsy.\nOverall, two patients had biopsy proven leucocytoclastic vasculitis, three were clinically diagnosed with vasculitis but did not have biopsy confirmation and two had biopsies, which revealed other pathologies (erythema nodosum and capillaritis), giving an overall prevalence of cutaneous vasculitis in patients with Burkholderia cepacia complex of 16.7%. Out of the five patients with vasculitis, three had a raised ESR/CRP ratio.\nThere was no evidence of renal involvement in any patient – all had a negative urine dipstick and normal serum creatinine. The antinuclear antibody and antineutrophil cytoplasmic antibody were negative in all patients apart from one with biopsy proven leucocytoclastic vasculitis who had a transiently positive antineutrophil cytoplasmic antibody. Antistreptolysin O titre was tested in only two out of the five patients and was negative.\nMean forced expiratory volume1 was 30% (range: 18–55) of the predicted value. In four patients (57%), the forced expiratory volume1 was lower at the time of presentation with rash compared to the baseline forced expiratory volume1 values for the previous two years.\nAll patients received antibiotics for a presumed pulmonary exacerbation at onset of the rash. Three patients received specific treatment for vasculitis (prednisolone ± additional immunosuppressive) after non-resolution of the rash.

Write a detailed clinical case vignette based on the following key phrases: Infectious diseases, Bacterial infections, Rare diseases

A 26-year-old female with B. cenocepecia presented with a history of recurrent small joint pains in association with intermittent painful erythematous nodular rash on the lower legs. This came on at the onset of an infective exacerbation of her chest. Biopsy confirmed erythema nodosum. Other causes of erythema nodosum were excluded, and she did not respond to Non-steroidal anti-inflammatory medications. Her symptoms continue to relapse in association with infective exacerbations of her chest.\nOf the remaining patients (n = 3), one presented with an erythematous rash on the lower legs and another had a purpuric rash on the lower legs and both were diagnosed clinically as leucocytoclastic vasculitis by a dermatologist. The third patient presented with purpuric areas and blistering of the lower legs which was confirmed as leucocytoclastic vasculitis on biopsy.\nOverall, two patients had biopsy proven leucocytoclastic vasculitis, three were clinically diagnosed with vasculitis but did not have biopsy confirmation and two had biopsies, which revealed other pathologies (erythema nodosum and capillaritis), giving an overall prevalence of cutaneous vasculitis in patients with Burkholderia cepacia complex of 16.7%. Out of the five patients with vasculitis, three had a raised ESR/CRP ratio.\nThere was no evidence of renal involvement in any patient – all had a negative urine dipstick and normal serum creatinine. The antinuclear antibody and antineutrophil cytoplasmic antibody were negative in all patients apart from one with biopsy proven leucocytoclastic vasculitis who had a transiently positive antineutrophil cytoplasmic antibody. Antistreptolysin O titre was tested in only two out of the five patients and was negative.\nMean forced expiratory volume1 was 30% (range: 18–55) of the predicted value. In four patients (57%), the forced expiratory volume1 was lower at the time of presentation with rash compared to the baseline forced expiratory volume1 values for the previous two years.\nAll patients received antibiotics for a presumed pulmonary exacerbation at onset of the rash. Three patients received specific treatment for vasculitis (prednisolone ± additional immunosuppressive) after non-resolution of the rash.

A 32-year-old male with a history of B. cenocepacia and Burkholderia multivorans developed an erythematous rash on the lower legs associated with an infective exacerbation of his chest. The rash resolved leaving grey discolouration but would occasionally flare up in the summer months. The biopsy showed features of capillaritis, and he was managed with topical steroids and compression hosiery.

Write a detailed clinical case vignette based on the following key phrases: Infectious diseases, Bacterial infections, Rare diseases

A 26-year-old female with B. cenocepecia presented with a history of recurrent small joint pains in association with intermittent painful erythematous nodular rash on the lower legs. This came on at the onset of an infective exacerbation of her chest. Biopsy confirmed erythema nodosum. Other causes of erythema nodosum were excluded, and she did not respond to Non-steroidal anti-inflammatory medications. Her symptoms continue to relapse in association with infective exacerbations of her chest.\nOf the remaining patients (n = 3), one presented with an erythematous rash on the lower legs and another had a purpuric rash on the lower legs and both were diagnosed clinically as leucocytoclastic vasculitis by a dermatologist. The third patient presented with purpuric areas and blistering of the lower legs which was confirmed as leucocytoclastic vasculitis on biopsy.\nOverall, two patients had biopsy proven leucocytoclastic vasculitis, three were clinically diagnosed with vasculitis but did not have biopsy confirmation and two had biopsies, which revealed other pathologies (erythema nodosum and capillaritis), giving an overall prevalence of cutaneous vasculitis in patients with Burkholderia cepacia complex of 16.7%. Out of the five patients with vasculitis, three had a raised ESR/CRP ratio.\nThere was no evidence of renal involvement in any patient – all had a negative urine dipstick and normal serum creatinine. The antinuclear antibody and antineutrophil cytoplasmic antibody were negative in all patients apart from one with biopsy proven leucocytoclastic vasculitis who had a transiently positive antineutrophil cytoplasmic antibody. Antistreptolysin O titre was tested in only two out of the five patients and was negative.\nMean forced expiratory volume1 was 30% (range: 18–55) of the predicted value. In four patients (57%), the forced expiratory volume1 was lower at the time of presentation with rash compared to the baseline forced expiratory volume1 values for the previous two years.\nAll patients received antibiotics for a presumed pulmonary exacerbation at onset of the rash. Three patients received specific treatment for vasculitis (prednisolone ± additional immunosuppressive) after non-resolution of the rash.

A 23-year-old female with B. cenocepacia developed an erythematous maculopapular rash on the lower legs with associated arthropathy of her finger joints. This was clinically felt to be reactive leucocytoclastic vaculitis and a biopsy was not conducted. The vasculitis did not respond initially to oral prednisolone, and she was then commenced on azathioprine and the rash responded to this. Two years later, she died following a severe infective exacerbation of her chest.

Write a detailed clinical case vignette based on the following key phrases: Infectious diseases, Bacterial infections, Rare diseases

A 42 year old diabetic woman from North Western Province of Sri Lanka presented with abdominal pain, vomiting and intermittent fever for one month. She had recurrent skin abscesses 6 months before presentation which was treated with incision and drainage and a short course of antibiotics for which there was only partial improvement. Three months before presentation to us she was found to have multiple liver abscesses which were aspirated in a local hospital. The aspirate grew “coliforms” resistant to gentamicin and sensitive to ceftazidime. She was treated with cefuroxime, meropenem, co-amoxyclav and metronidazole; further identification of the organism was not done at the local hospital.\nOn presentation to us she had high fever and tender hepatomegaly. Her body weight was 40 kg. Rest of the examination including nervous system was normal.\nHer full blood count showed leukocytosis [15.7×109/L] and granulocytosis [11.3 × 109/L], ESR was 100 mm in the 1st hour and C-reactive protein was 98.4 mg/L. Ultra sound scan of abdomen showed multiple liver and splenic abscesses.\nPresence of recurrent multiple liver and splenic abscesses in a diabetic patient who had recurrent skin abscess in the past made us consider melioidosis in the differential diagnosis. Intravenous meropenem 2g eight hourly was started empirically and aspirate was sent with a sample of serum to Faculty of Medicine, University of Colombo which serves as the National Reference Laboratory, to confirm the diagnosis. There the aspirate yielded pinpoint colonies on blood, chocolate and Macconkey agar after overnight incubation. Since biochemical panels are not very accurate in diagnosis of Burkholderia pseudomallei, isolate was subjected to PCR which confirmed the diagnosis.\nSerum antibodies to melioidin antigen using an in-house indirect haemagglutination (IHA) test based on that described by Alexander et al. with antigen prepared from local strains of B.pseudomallei [] were positive at a titre of 1:10240.\nAfter confirmation of melioidosis intravenous meropenem was continued. However after a week of treatment the disease course was complicated by bilateral lower limb weakness which progressed over the next 4 days. Her lower limbs were flaccid and deep tendon reflexes were absent. There was no sensory sign or bladder/bowel involvement. Cerebro-spinal fluid analysis showed protein of 114.5 mg/dl, glucose 62 mg/dl, white cells <10 mm9/L and red cells < 10 mm9/L. MRI scan of the brain was normal. The nerve conduction study showed evidence of severe peripheral neuropathy with axonal degeneration; compatible with a primary axonal type inflammatory neuropathy such as acute motor axonal neuropathy or acute sensory motor axonal neuropathy.\nA diagnosis of Guillan-Barre syndrome was made based on Brighton case definition (Table ) () and she was treated with 4 cycles of plasmapharesis on alternate days for which there was marked improvement of neurological deficit.\nWith intravenous meropenem patient further improved and her ESR and CRP became normal. Repeat ultrasound scan of abdomen showed reduction of the size of liver and splenic abscesses.\nEradication therapy with cotrimoxazole 1920 mg 12 hourly and co-amoxyclav 625 mg 8 hourly was started on the seventh week and overlapped with intravenous antibiotic for further two weeks. Patient was discharged to outpatient clinic after two weeks of oral antibiotics with a plan to continue them for12 weeks. At the end of 12 weeks she had no residual neurological weakness and there was no sign of a relapse.

A 26-year-old female with B. cenocepecia presented with a history of recurrent small joint pains in association with intermittent painful erythematous nodular rash on the lower legs. This came on at the onset of an infective exacerbation of her chest. Biopsy confirmed erythema nodosum. Other causes of erythema nodosum were excluded, and she did not respond to Non-steroidal anti-inflammatory medications. Her symptoms continue to relapse in association with infective exacerbations of her chest.\nOf the remaining patients (n = 3), one presented with an erythematous rash on the lower legs and another had a purpuric rash on the lower legs and both were diagnosed clinically as leucocytoclastic vasculitis by a dermatologist. The third patient presented with purpuric areas and blistering of the lower legs which was confirmed as leucocytoclastic vasculitis on biopsy.\nOverall, two patients had biopsy proven leucocytoclastic vasculitis, three were clinically diagnosed with vasculitis but did not have biopsy confirmation and two had biopsies, which revealed other pathologies (erythema nodosum and capillaritis), giving an overall prevalence of cutaneous vasculitis in patients with Burkholderia cepacia complex of 16.7%. Out of the five patients with vasculitis, three had a raised ESR/CRP ratio.\nThere was no evidence of renal involvement in any patient – all had a negative urine dipstick and normal serum creatinine. The antinuclear antibody and antineutrophil cytoplasmic antibody were negative in all patients apart from one with biopsy proven leucocytoclastic vasculitis who had a transiently positive antineutrophil cytoplasmic antibody. Antistreptolysin O titre was tested in only two out of the five patients and was negative.\nMean forced expiratory volume1 was 30% (range: 18–55) of the predicted value. In four patients (57%), the forced expiratory volume1 was lower at the time of presentation with rash compared to the baseline forced expiratory volume1 values for the previous two years.\nAll patients received antibiotics for a presumed pulmonary exacerbation at onset of the rash. Three patients received specific treatment for vasculitis (prednisolone ± additional immunosuppressive) after non-resolution of the rash.

Write a detailed clinical case vignette based on the following key phrases: Infectious diseases, Bacterial infections, Rare diseases

We present the case of a 15-year-old female heterozygous for ΔF508del/N1303K, with poorly controlled lung disease determined by forced expiratory volume in one second (FEV1) 44% of predicted value, who presented with cutaneous vasculitis and arthritis in association with an infective exacerbation of CF. The cutaneous involvement consisted of a palpable purpuric rash distributed over the tibial surfaces, ankles, and dorsa of the feet (Figure ). At this admission in 2015, infection and colonization with BCC and methicillin-resistant Staphylococcus aureus (MRSA) later in the year were also diagnosed. Blood work at admission is presented in Table ; acute phase reactants (C-reactive protein and fibrinogen) and rheumatoid factor were elevated. ANCAs were negative. Antinuclear antibodies (ANAs) were negative initially, but became positive five years later. Over the next several years, the patient required on average three to four hospitalizations every year due to IECF. Cutaneous vasculitis was present in approximately every other episode of IECF and improved with treatment of the pulmonary exacerbations. Bacterial colonization together with respiratory function is summarized in Figure - of note, the FEV1 decreased from 65% at 14 years of age (before appearance of the vasculitis) to 24% by 19 years of age.\nFrom the patient’s medical history, we consider eloquent the following facts: at the age of two years, she received nine-month isoniazid prophylaxis due to contact with her father who had tuberculosis. At the age of three years, she was diagnosed with bronchiectasis via CT. At the age of nine years, colonization with Pseudomonas aeruginosa was diagnosed through bronchoalveolar lavage and she had an FEV1 of 75% predicted. At the age of 13 years, the patient was diagnosed with a latent pulmonary tuberculosis infection which was again treated with nine months of isoniazid monotherapy. At the age of 14 years, she was diagnosed with allergic bronchopulmonary aspergillosis, via elevated total IgE and Aspergillus-specific IgE. At this time, the patient had an FEV1 of 65% predicted.\nAt the age of 15 years (2015), colonization with BCC was noted, she had an FEV1 of 44% predicted. At this time, the patient showed first signs of the cutaneous vasculitis, in form of a palpable purpuric, nonvesicular maculopapular rash localized to the lower legs. The lower extremities were slightly swollen, painful, and as the episodes of the vasculitis continued to erupt, grey discoloration in the place of the rash began to set in and over the years became permanent. At the age of 18 years (2018), colonization with Achromobacter xylosoxidans and Candida parapsilosis was noted, she had an FEV1 of 24% during the exacerbation, which improved to 38% of predicted after treatment. The chest x-ray comparison from 2015 to 2017 is presented in Figure and B, respectively. The CT scan done at this time showed cystic dilations in the right apex (Figure ) and severe bilateral middle lung field cylindrical bronchiectasis with signet-ring signs (Figure ).\nTreatment was started with long-term oral prednisone. Colonization with Pseudomonas, BCC, MRSA, Achromobacter xylosoxidans, and Candida parapsilosis was treated with multiple courses of inhaled, IV and oral antibiotics (linezolid, ceftazidime, ofloxacin) and antifungals (fluconazole and voriconasole). In addition, the following was administered: azithromycin (three days a week for three months), tiotropium, an antihistamine, and periodic cough assist with antibiotic aerosol treatment. Starting from 2019, the patient’s nebulization with colistin and tobramycin was supplemented with nightly positive-pressure ventilation (PPV), but the ventilation was discontinued six months later due to slight hemoptysis that was predominantly present in the morning. Throughout the six months, the patient was on PPV, she experienced twp IECF, which required hospitalization. The two episodes of IECF, together with the extensive bronchiectasis, may have contributed to the appearance of the hemoptysis, which may have predisposed certain areas of the lung to barotrauma. After the PPV was discontinued, the hemoptysis disappeared and did not require any more treatment.

A 42-year-old Sri Lankan man presented to the Colombo North Teaching Hospital, Ragama, Sri Lanka (CNTH) with a febrile illness of 6 days, accompanied by headache and constitutional symptoms. He was a grocer from Minuwangoda, a suburban area in the Western Province situated 44 km from Colombo. He was initially investigated and treated at a regional hospital for 4 days, and was transferred to the CNTH for specialized care. He gave a history of type 2 diabetes mellitus for 5 years without microvascular or macrovascular complications, and was a nonsmoker and a teetotaler. There were no specific symptoms suggesting a source of infection such as cough, abdominal pain, urinary symptoms, etc. He was febrile with a temperature of 39.10 C, and examination of the heart, lungs and abdomen was unremarkable. There was no papilloedema, focal neurological signs, pyramidal signs or neck stiffness. Initial laboratory work up revealed features of a bacterial infection, with neutrophil leukocytosis and elevated inflammatory markers (erythrocyte sedimentation rate – 101 mm/1st hour, C-reactive protein - 220 mg/dl). Initial blood cultures done at the regional hospital had yielded an isolate, which was reported as a Pseudomonas species; this was sensitive to ceftazidime, imipenem and meropenem and resistant to gentamicin and ceftriaxone. Other basic laboratory investigations including renal and liver function tests, electrolyte panel and urinalysis were normal. Chest x-ray and ultrasound scan of the abdomen were normal, and the trans-thoracic 2-D echo did not show any vegetations. As the unusual antibiotic sensitivity pattern suggested the possibility of melioidosis, blood was sent for serological testing to a specialized Melioidosis Research Laboratory at the Faculty of Medicine, University of Colombo.\nHe had been initially treated with intravenous ceftriaxone, and later with ceftazidime according to the antibiotic sensitivity pattern. Although the frequency and intensity of fever spikes reduced with treatment, he continued to have low grade fever and complain of anorexia, malaise and lethargy. On the 4th day after admission to the CNTH (day 10 of the illness), he developed simple partial seizures involving the left lower limb, progressing to persistent numbness of the left side of the body. An urgent CT scan of the head revealed a subdural collection over the right fronto-parietal region with gas locules and obliteration of sulci and gyri, without definite evidence of abscess formation (Fig. ). Contrast enhanced MRI scan of the brain demonstrated a subdural collection in the right fronto-temporo-parietal region with possible abscess formation in the right parietal region (Fig. ). Seizures were treated with oral sodium valproate and phenytoin sodium. He was referred for neurosurgical opinion, and the subdural collection was managed conservatively. Results of the indirect hemagglutination assay (IHA) for melioidosis antibodies were received on the following day; an antibody titre of more than 1/10,240 was strongly suggestive of an acute infection with Burkhoderia pseudomallei and a diagnosis of cerebral melioidosis was made.\nAntibiotics were changed to intravenous meropenem and oral trimethoprim/sulfamethoxazole (Co-trimoxazole/TMP-SMX). Initial intensive therapy with these antibiotics was continued for 8 weeks, until clinical improvement was evident with resolution of inflammatory markers and radiological improvement confirmed by repeat MRI scan of the brain. (Fig. ) Repeat blood cultures were sterile after 2 weeks of treatment with antibiotics. There were no further seizures, and the fever and the neurological symptoms resolved completely. He was discharged home with oral TMP-SMX and doxycycline, which were continued for 6 months, and the antiepileptics were gradually tailed off. At 6 months follow up he was asymptomatic. (Fig. ).

Write a detailed clinical case vignette based on the following key phrases: Infectious diseases, Bacterial infections, Rare diseases

We present the case of a 15-year-old female heterozygous for ΔF508del/N1303K, with poorly controlled lung disease determined by forced expiratory volume in one second (FEV1) 44% of predicted value, who presented with cutaneous vasculitis and arthritis in association with an infective exacerbation of CF. The cutaneous involvement consisted of a palpable purpuric rash distributed over the tibial surfaces, ankles, and dorsa of the feet (Figure ). At this admission in 2015, infection and colonization with BCC and methicillin-resistant Staphylococcus aureus (MRSA) later in the year were also diagnosed. Blood work at admission is presented in Table ; acute phase reactants (C-reactive protein and fibrinogen) and rheumatoid factor were elevated. ANCAs were negative. Antinuclear antibodies (ANAs) were negative initially, but became positive five years later. Over the next several years, the patient required on average three to four hospitalizations every year due to IECF. Cutaneous vasculitis was present in approximately every other episode of IECF and improved with treatment of the pulmonary exacerbations. Bacterial colonization together with respiratory function is summarized in Figure - of note, the FEV1 decreased from 65% at 14 years of age (before appearance of the vasculitis) to 24% by 19 years of age.\nFrom the patient’s medical history, we consider eloquent the following facts: at the age of two years, she received nine-month isoniazid prophylaxis due to contact with her father who had tuberculosis. At the age of three years, she was diagnosed with bronchiectasis via CT. At the age of nine years, colonization with Pseudomonas aeruginosa was diagnosed through bronchoalveolar lavage and she had an FEV1 of 75% predicted. At the age of 13 years, the patient was diagnosed with a latent pulmonary tuberculosis infection which was again treated with nine months of isoniazid monotherapy. At the age of 14 years, she was diagnosed with allergic bronchopulmonary aspergillosis, via elevated total IgE and Aspergillus-specific IgE. At this time, the patient had an FEV1 of 65% predicted.\nAt the age of 15 years (2015), colonization with BCC was noted, she had an FEV1 of 44% predicted. At this time, the patient showed first signs of the cutaneous vasculitis, in form of a palpable purpuric, nonvesicular maculopapular rash localized to the lower legs. The lower extremities were slightly swollen, painful, and as the episodes of the vasculitis continued to erupt, grey discoloration in the place of the rash began to set in and over the years became permanent. At the age of 18 years (2018), colonization with Achromobacter xylosoxidans and Candida parapsilosis was noted, she had an FEV1 of 24% during the exacerbation, which improved to 38% of predicted after treatment. The chest x-ray comparison from 2015 to 2017 is presented in Figure and B, respectively. The CT scan done at this time showed cystic dilations in the right apex (Figure ) and severe bilateral middle lung field cylindrical bronchiectasis with signet-ring signs (Figure ).\nTreatment was started with long-term oral prednisone. Colonization with Pseudomonas, BCC, MRSA, Achromobacter xylosoxidans, and Candida parapsilosis was treated with multiple courses of inhaled, IV and oral antibiotics (linezolid, ceftazidime, ofloxacin) and antifungals (fluconazole and voriconasole). In addition, the following was administered: azithromycin (three days a week for three months), tiotropium, an antihistamine, and periodic cough assist with antibiotic aerosol treatment. Starting from 2019, the patient’s nebulization with colistin and tobramycin was supplemented with nightly positive-pressure ventilation (PPV), but the ventilation was discontinued six months later due to slight hemoptysis that was predominantly present in the morning. Throughout the six months, the patient was on PPV, she experienced twp IECF, which required hospitalization. The two episodes of IECF, together with the extensive bronchiectasis, may have contributed to the appearance of the hemoptysis, which may have predisposed certain areas of the lung to barotrauma. After the PPV was discontinued, the hemoptysis disappeared and did not require any more treatment.

In February 2006, a previously healthy 58-year-old Sinhalese woman presented to our hospital with a history of intermittent fever, headache, loss of appetite, loss of weight, dry cough, and arthralgia of 5 weeks’ duration. She had no known past medical conditions or any family history of chronic disorders or similar illnesses. She was a housewife who frequently engaged in gardening and had no history of visits to forest areas or working in paddy fields. She was not alcoholic and was a nonsmoker.\nAt the beginning, she had been hospitalized, had undergone investigations, and had received broad-spectrum antibiotics. Due to the nature of the protracted illness with fever, and because she had an erythrocyte sedimentation rate (ESR) above 100 mm/h and increased C-reactive protein (CRP), a course of antituberculous antibiotics had been given over 2 weeks without definitive confirmation of the diagnosis of tuberculosis. While on antituberculous medications, instead of clinical improvement, she showed further deterioration of her illness and developed new problems, including appearance of a tender lump over the right temporal area over the course of 1 week and another similar lump over the anterior aspect of the left thigh of 5 days’ duration. At this juncture, she left the first hospital at her own wish and secured admission to Teaching Hospital Peradeniya (THP).\nOn admission to THP, she looked very ill and feeble and was febrile and tachypneic. She had a tender lump resembling an abscess over the right temporal area. Furthermore, she had similar lumps over the anterior aspect of the left thigh. She had an inflamed, swollen knee and wrist joints with a tender erythematous rash over both shins that resembled erythema nodosum. Her pulse rate was 110 beats/min with blood pressure of 100/65 mmHg. The results of her respiratory system and abdominal examinations were clinically normal. She was conscious, rational, and had no neck stiffness, with a clinically normal neurological examination result.\nBlood samples were taken for basic investigations and culture at this juncture. Diagnostic needle aspirates from the cystic lumps and knee joint effusions were purulent and were sent for bacteriological investigations. Blood samples for cultures were taken under aseptic conditions. Three separate blood cultures were taken in 30-minutes intervals and drawn into standard blood culture bottles. Knee joint and skin lump aspirates also were drawn into separate culture bottles under aseptic conditions. All the samples were transported to the microbiology laboratory, which is located within the hospital premises, and the cultures were done by a consultant microbiologist. Pending investigations, the patient was treated with intravenous (IV) co-amoxiclav (amoxicillin mixed with clavulanic acid).\nOn the fifth day of the patient’s admission, she became drowsy and developed focal seizures involving the right upper and lower limbs and lasting for around 2 minutes. She became drowsy with a Glasgow Coma Scale (GCS) score of 12/15. She moved all her limbs, and her deep tendon reflexes were normal, but she had an upgoing plantar response. She had no neck stiffness, positive Kernig sign, or focal neurological signs. She had persistent tachycardia with low blood pressure of 90/50 mmHg. Her respiratory rate was 30 breaths/min, and she had bibasal crepitations. She had bilateral knee joint effusions, and her knee joints were swollen, warm, erythematous, and tender. A tentative diagnosis of cerebral abscesses was made, and the patient was transferred to the intensive care unit.\nUrgent contrast-enhanced computed tomography of the brain showed a well-defined cystic mass in the right temporal region outside the skull vault and contrast-enhanced changes in the adjacent brain matter. Furthermore, a 12-lead electroencephalogram (EEG) showed a theta-wave focus over the right temporal area with intermittent epileptiform discharges compatible with structural brain damage. The results of her ultrasound examination of the abdomen and an echocardiogram were normal. Her white blood cell count was 3.3 × 109/L with neutrophils of 83% and lymphocytes of 12%. Her ESR was 120 mm/first hour, and her CRP level was 192 mg/L. Her chest x-ray showed multiple peripherally located, ill-defined cystic areas in both lung fields, more in the lung bases, suggestive of multiple lung abscesses. By that time, the blood culture, knee joint aspirate, and skin lump aspirates grew B. pseudomallei, which was confirmed by the local microbiologists with the help of international reference laboratories []. Thus, a diagnosis of melioidosis was confirmed, and treatment commenced.\nFollowing the confirmed diagnosis her antibiotic regimen was changed and started on IV meropenem 1 g 8-hourly for 8 days and later changed to IV imipenem 500 mg 6-hourly, based on the antibiotic sensitivity pattern of the bacterial isolate. Two more antibiotics were added to the regimen at the same time: IV ciprofloxacin 400 mg 12-hourly and IV ceftazidime 2 g 6-hourly. The patient showed gradual improvement of her general condition, and her fever subsided in a few days. However, all three antibiotics were continued for 30 days and changed to an oral antibiotic course comprising cotrimoxazole 1920 mg twice daily plus doxycycline 100 mg twice daily for 20 more weeks. Her seizures were controlled with sodium valproate 200 mg thrice daily. In follow-up, the patient’s chest x-ray, ESR (50 mm/h), CRP (0.7 mg/dl), and liver and renal profiles showed gradual improvement, and the results of her retroviral screening were negative. Her blood sugar and hemoglobin A1c levels were within normal limits. The result of repeat EEG in 3 months’ time was normal, and the patient’s sodium valproate was gradually tapered. After 6 months of antibiotic treatment, her ESR was 12 mm/first hour; her CRP was < 6 mg/L; and all of her other biochemical parameters were normal. Then, she was advised to come back to our hospital for annual screening to check for recurrence of the disease, including ESR and CRP measurement. She has had no recurrence of her illness during the last 13 years and remains well.\nSubsequently, how she contracted the infection was inquired about. She was able to recall contact with soil a few days prior to developing her illness. The footpath leading to her home had a side drain that was filled with mud and soil. She found that a worker had dug up the drain and piled mud and soil on the footpath. The patient, dismantled the piled-up soil with her bare feet and made the footpath accessible.

Write a detailed clinical case vignette based on the following key phrases: Infectious diseases, Bacterial infections, Rare diseases

We present the case of a 15-year-old female heterozygous for ΔF508del/N1303K, with poorly controlled lung disease determined by forced expiratory volume in one second (FEV1) 44% of predicted value, who presented with cutaneous vasculitis and arthritis in association with an infective exacerbation of CF. The cutaneous involvement consisted of a palpable purpuric rash distributed over the tibial surfaces, ankles, and dorsa of the feet (Figure ). At this admission in 2015, infection and colonization with BCC and methicillin-resistant Staphylococcus aureus (MRSA) later in the year were also diagnosed. Blood work at admission is presented in Table ; acute phase reactants (C-reactive protein and fibrinogen) and rheumatoid factor were elevated. ANCAs were negative. Antinuclear antibodies (ANAs) were negative initially, but became positive five years later. Over the next several years, the patient required on average three to four hospitalizations every year due to IECF. Cutaneous vasculitis was present in approximately every other episode of IECF and improved with treatment of the pulmonary exacerbations. Bacterial colonization together with respiratory function is summarized in Figure - of note, the FEV1 decreased from 65% at 14 years of age (before appearance of the vasculitis) to 24% by 19 years of age.\nFrom the patient’s medical history, we consider eloquent the following facts: at the age of two years, she received nine-month isoniazid prophylaxis due to contact with her father who had tuberculosis. At the age of three years, she was diagnosed with bronchiectasis via CT. At the age of nine years, colonization with Pseudomonas aeruginosa was diagnosed through bronchoalveolar lavage and she had an FEV1 of 75% predicted. At the age of 13 years, the patient was diagnosed with a latent pulmonary tuberculosis infection which was again treated with nine months of isoniazid monotherapy. At the age of 14 years, she was diagnosed with allergic bronchopulmonary aspergillosis, via elevated total IgE and Aspergillus-specific IgE. At this time, the patient had an FEV1 of 65% predicted.\nAt the age of 15 years (2015), colonization with BCC was noted, she had an FEV1 of 44% predicted. At this time, the patient showed first signs of the cutaneous vasculitis, in form of a palpable purpuric, nonvesicular maculopapular rash localized to the lower legs. The lower extremities were slightly swollen, painful, and as the episodes of the vasculitis continued to erupt, grey discoloration in the place of the rash began to set in and over the years became permanent. At the age of 18 years (2018), colonization with Achromobacter xylosoxidans and Candida parapsilosis was noted, she had an FEV1 of 24% during the exacerbation, which improved to 38% of predicted after treatment. The chest x-ray comparison from 2015 to 2017 is presented in Figure and B, respectively. The CT scan done at this time showed cystic dilations in the right apex (Figure ) and severe bilateral middle lung field cylindrical bronchiectasis with signet-ring signs (Figure ).\nTreatment was started with long-term oral prednisone. Colonization with Pseudomonas, BCC, MRSA, Achromobacter xylosoxidans, and Candida parapsilosis was treated with multiple courses of inhaled, IV and oral antibiotics (linezolid, ceftazidime, ofloxacin) and antifungals (fluconazole and voriconasole). In addition, the following was administered: azithromycin (three days a week for three months), tiotropium, an antihistamine, and periodic cough assist with antibiotic aerosol treatment. Starting from 2019, the patient’s nebulization with colistin and tobramycin was supplemented with nightly positive-pressure ventilation (PPV), but the ventilation was discontinued six months later due to slight hemoptysis that was predominantly present in the morning. Throughout the six months, the patient was on PPV, she experienced twp IECF, which required hospitalization. The two episodes of IECF, together with the extensive bronchiectasis, may have contributed to the appearance of the hemoptysis, which may have predisposed certain areas of the lung to barotrauma. After the PPV was discontinued, the hemoptysis disappeared and did not require any more treatment.

A 32-year-old male with a history of B. cenocepacia and Burkholderia multivorans developed an erythematous rash on the lower legs associated with an infective exacerbation of his chest. The rash resolved leaving grey discolouration but would occasionally flare up in the summer months. The biopsy showed features of capillaritis, and he was managed with topical steroids and compression hosiery.

Write a detailed clinical case vignette based on the following key phrases: Infectious diseases, Bacterial infections, Rare diseases

We present the case of a 15-year-old female heterozygous for ΔF508del/N1303K, with poorly controlled lung disease determined by forced expiratory volume in one second (FEV1) 44% of predicted value, who presented with cutaneous vasculitis and arthritis in association with an infective exacerbation of CF. The cutaneous involvement consisted of a palpable purpuric rash distributed over the tibial surfaces, ankles, and dorsa of the feet (Figure ). At this admission in 2015, infection and colonization with BCC and methicillin-resistant Staphylococcus aureus (MRSA) later in the year were also diagnosed. Blood work at admission is presented in Table ; acute phase reactants (C-reactive protein and fibrinogen) and rheumatoid factor were elevated. ANCAs were negative. Antinuclear antibodies (ANAs) were negative initially, but became positive five years later. Over the next several years, the patient required on average three to four hospitalizations every year due to IECF. Cutaneous vasculitis was present in approximately every other episode of IECF and improved with treatment of the pulmonary exacerbations. Bacterial colonization together with respiratory function is summarized in Figure - of note, the FEV1 decreased from 65% at 14 years of age (before appearance of the vasculitis) to 24% by 19 years of age.\nFrom the patient’s medical history, we consider eloquent the following facts: at the age of two years, she received nine-month isoniazid prophylaxis due to contact with her father who had tuberculosis. At the age of three years, she was diagnosed with bronchiectasis via CT. At the age of nine years, colonization with Pseudomonas aeruginosa was diagnosed through bronchoalveolar lavage and she had an FEV1 of 75% predicted. At the age of 13 years, the patient was diagnosed with a latent pulmonary tuberculosis infection which was again treated with nine months of isoniazid monotherapy. At the age of 14 years, she was diagnosed with allergic bronchopulmonary aspergillosis, via elevated total IgE and Aspergillus-specific IgE. At this time, the patient had an FEV1 of 65% predicted.\nAt the age of 15 years (2015), colonization with BCC was noted, she had an FEV1 of 44% predicted. At this time, the patient showed first signs of the cutaneous vasculitis, in form of a palpable purpuric, nonvesicular maculopapular rash localized to the lower legs. The lower extremities were slightly swollen, painful, and as the episodes of the vasculitis continued to erupt, grey discoloration in the place of the rash began to set in and over the years became permanent. At the age of 18 years (2018), colonization with Achromobacter xylosoxidans and Candida parapsilosis was noted, she had an FEV1 of 24% during the exacerbation, which improved to 38% of predicted after treatment. The chest x-ray comparison from 2015 to 2017 is presented in Figure and B, respectively. The CT scan done at this time showed cystic dilations in the right apex (Figure ) and severe bilateral middle lung field cylindrical bronchiectasis with signet-ring signs (Figure ).\nTreatment was started with long-term oral prednisone. Colonization with Pseudomonas, BCC, MRSA, Achromobacter xylosoxidans, and Candida parapsilosis was treated with multiple courses of inhaled, IV and oral antibiotics (linezolid, ceftazidime, ofloxacin) and antifungals (fluconazole and voriconasole). In addition, the following was administered: azithromycin (three days a week for three months), tiotropium, an antihistamine, and periodic cough assist with antibiotic aerosol treatment. Starting from 2019, the patient’s nebulization with colistin and tobramycin was supplemented with nightly positive-pressure ventilation (PPV), but the ventilation was discontinued six months later due to slight hemoptysis that was predominantly present in the morning. Throughout the six months, the patient was on PPV, she experienced twp IECF, which required hospitalization. The two episodes of IECF, together with the extensive bronchiectasis, may have contributed to the appearance of the hemoptysis, which may have predisposed certain areas of the lung to barotrauma. After the PPV was discontinued, the hemoptysis disappeared and did not require any more treatment.

A 23-year-old female with B. cenocepacia developed an erythematous maculopapular rash on the lower legs with associated arthropathy of her finger joints. This was clinically felt to be reactive leucocytoclastic vaculitis and a biopsy was not conducted. The vasculitis did not respond initially to oral prednisolone, and she was then commenced on azathioprine and the rash responded to this. Two years later, she died following a severe infective exacerbation of her chest.

Write a detailed clinical case vignette based on the following key phrases: Infectious diseases, Bacterial infections, Rare diseases

We present the case of a 15-year-old female heterozygous for ΔF508del/N1303K, with poorly controlled lung disease determined by forced expiratory volume in one second (FEV1) 44% of predicted value, who presented with cutaneous vasculitis and arthritis in association with an infective exacerbation of CF. The cutaneous involvement consisted of a palpable purpuric rash distributed over the tibial surfaces, ankles, and dorsa of the feet (Figure ). At this admission in 2015, infection and colonization with BCC and methicillin-resistant Staphylococcus aureus (MRSA) later in the year were also diagnosed. Blood work at admission is presented in Table ; acute phase reactants (C-reactive protein and fibrinogen) and rheumatoid factor were elevated. ANCAs were negative. Antinuclear antibodies (ANAs) were negative initially, but became positive five years later. Over the next several years, the patient required on average three to four hospitalizations every year due to IECF. Cutaneous vasculitis was present in approximately every other episode of IECF and improved with treatment of the pulmonary exacerbations. Bacterial colonization together with respiratory function is summarized in Figure - of note, the FEV1 decreased from 65% at 14 years of age (before appearance of the vasculitis) to 24% by 19 years of age.\nFrom the patient’s medical history, we consider eloquent the following facts: at the age of two years, she received nine-month isoniazid prophylaxis due to contact with her father who had tuberculosis. At the age of three years, she was diagnosed with bronchiectasis via CT. At the age of nine years, colonization with Pseudomonas aeruginosa was diagnosed through bronchoalveolar lavage and she had an FEV1 of 75% predicted. At the age of 13 years, the patient was diagnosed with a latent pulmonary tuberculosis infection which was again treated with nine months of isoniazid monotherapy. At the age of 14 years, she was diagnosed with allergic bronchopulmonary aspergillosis, via elevated total IgE and Aspergillus-specific IgE. At this time, the patient had an FEV1 of 65% predicted.\nAt the age of 15 years (2015), colonization with BCC was noted, she had an FEV1 of 44% predicted. At this time, the patient showed first signs of the cutaneous vasculitis, in form of a palpable purpuric, nonvesicular maculopapular rash localized to the lower legs. The lower extremities were slightly swollen, painful, and as the episodes of the vasculitis continued to erupt, grey discoloration in the place of the rash began to set in and over the years became permanent. At the age of 18 years (2018), colonization with Achromobacter xylosoxidans and Candida parapsilosis was noted, she had an FEV1 of 24% during the exacerbation, which improved to 38% of predicted after treatment. The chest x-ray comparison from 2015 to 2017 is presented in Figure and B, respectively. The CT scan done at this time showed cystic dilations in the right apex (Figure ) and severe bilateral middle lung field cylindrical bronchiectasis with signet-ring signs (Figure ).\nTreatment was started with long-term oral prednisone. Colonization with Pseudomonas, BCC, MRSA, Achromobacter xylosoxidans, and Candida parapsilosis was treated with multiple courses of inhaled, IV and oral antibiotics (linezolid, ceftazidime, ofloxacin) and antifungals (fluconazole and voriconasole). In addition, the following was administered: azithromycin (three days a week for three months), tiotropium, an antihistamine, and periodic cough assist with antibiotic aerosol treatment. Starting from 2019, the patient’s nebulization with colistin and tobramycin was supplemented with nightly positive-pressure ventilation (PPV), but the ventilation was discontinued six months later due to slight hemoptysis that was predominantly present in the morning. Throughout the six months, the patient was on PPV, she experienced twp IECF, which required hospitalization. The two episodes of IECF, together with the extensive bronchiectasis, may have contributed to the appearance of the hemoptysis, which may have predisposed certain areas of the lung to barotrauma. After the PPV was discontinued, the hemoptysis disappeared and did not require any more treatment.

A 42 year old diabetic woman from North Western Province of Sri Lanka presented with abdominal pain, vomiting and intermittent fever for one month. She had recurrent skin abscesses 6 months before presentation which was treated with incision and drainage and a short course of antibiotics for which there was only partial improvement. Three months before presentation to us she was found to have multiple liver abscesses which were aspirated in a local hospital. The aspirate grew “coliforms” resistant to gentamicin and sensitive to ceftazidime. She was treated with cefuroxime, meropenem, co-amoxyclav and metronidazole; further identification of the organism was not done at the local hospital.\nOn presentation to us she had high fever and tender hepatomegaly. Her body weight was 40 kg. Rest of the examination including nervous system was normal.\nHer full blood count showed leukocytosis [15.7×109/L] and granulocytosis [11.3 × 109/L], ESR was 100 mm in the 1st hour and C-reactive protein was 98.4 mg/L. Ultra sound scan of abdomen showed multiple liver and splenic abscesses.\nPresence of recurrent multiple liver and splenic abscesses in a diabetic patient who had recurrent skin abscess in the past made us consider melioidosis in the differential diagnosis. Intravenous meropenem 2g eight hourly was started empirically and aspirate was sent with a sample of serum to Faculty of Medicine, University of Colombo which serves as the National Reference Laboratory, to confirm the diagnosis. There the aspirate yielded pinpoint colonies on blood, chocolate and Macconkey agar after overnight incubation. Since biochemical panels are not very accurate in diagnosis of Burkholderia pseudomallei, isolate was subjected to PCR which confirmed the diagnosis.\nSerum antibodies to melioidin antigen using an in-house indirect haemagglutination (IHA) test based on that described by Alexander et al. with antigen prepared from local strains of B.pseudomallei [] were positive at a titre of 1:10240.\nAfter confirmation of melioidosis intravenous meropenem was continued. However after a week of treatment the disease course was complicated by bilateral lower limb weakness which progressed over the next 4 days. Her lower limbs were flaccid and deep tendon reflexes were absent. There was no sensory sign or bladder/bowel involvement. Cerebro-spinal fluid analysis showed protein of 114.5 mg/dl, glucose 62 mg/dl, white cells <10 mm9/L and red cells < 10 mm9/L. MRI scan of the brain was normal. The nerve conduction study showed evidence of severe peripheral neuropathy with axonal degeneration; compatible with a primary axonal type inflammatory neuropathy such as acute motor axonal neuropathy or acute sensory motor axonal neuropathy.\nA diagnosis of Guillan-Barre syndrome was made based on Brighton case definition (Table ) () and she was treated with 4 cycles of plasmapharesis on alternate days for which there was marked improvement of neurological deficit.\nWith intravenous meropenem patient further improved and her ESR and CRP became normal. Repeat ultrasound scan of abdomen showed reduction of the size of liver and splenic abscesses.\nEradication therapy with cotrimoxazole 1920 mg 12 hourly and co-amoxyclav 625 mg 8 hourly was started on the seventh week and overlapped with intravenous antibiotic for further two weeks. Patient was discharged to outpatient clinic after two weeks of oral antibiotics with a plan to continue them for12 weeks. At the end of 12 weeks she had no residual neurological weakness and there was no sign of a relapse.

Write a detailed clinical case vignette based on the following key phrases: Infectious diseases, Bacterial infections, Rare diseases

A 42-year-old Sri Lankan man presented to the Colombo North Teaching Hospital, Ragama, Sri Lanka (CNTH) with a febrile illness of 6 days, accompanied by headache and constitutional symptoms. He was a grocer from Minuwangoda, a suburban area in the Western Province situated 44 km from Colombo. He was initially investigated and treated at a regional hospital for 4 days, and was transferred to the CNTH for specialized care. He gave a history of type 2 diabetes mellitus for 5 years without microvascular or macrovascular complications, and was a nonsmoker and a teetotaler. There were no specific symptoms suggesting a source of infection such as cough, abdominal pain, urinary symptoms, etc. He was febrile with a temperature of 39.10 C, and examination of the heart, lungs and abdomen was unremarkable. There was no papilloedema, focal neurological signs, pyramidal signs or neck stiffness. Initial laboratory work up revealed features of a bacterial infection, with neutrophil leukocytosis and elevated inflammatory markers (erythrocyte sedimentation rate – 101 mm/1st hour, C-reactive protein - 220 mg/dl). Initial blood cultures done at the regional hospital had yielded an isolate, which was reported as a Pseudomonas species; this was sensitive to ceftazidime, imipenem and meropenem and resistant to gentamicin and ceftriaxone. Other basic laboratory investigations including renal and liver function tests, electrolyte panel and urinalysis were normal. Chest x-ray and ultrasound scan of the abdomen were normal, and the trans-thoracic 2-D echo did not show any vegetations. As the unusual antibiotic sensitivity pattern suggested the possibility of melioidosis, blood was sent for serological testing to a specialized Melioidosis Research Laboratory at the Faculty of Medicine, University of Colombo.\nHe had been initially treated with intravenous ceftriaxone, and later with ceftazidime according to the antibiotic sensitivity pattern. Although the frequency and intensity of fever spikes reduced with treatment, he continued to have low grade fever and complain of anorexia, malaise and lethargy. On the 4th day after admission to the CNTH (day 10 of the illness), he developed simple partial seizures involving the left lower limb, progressing to persistent numbness of the left side of the body. An urgent CT scan of the head revealed a subdural collection over the right fronto-parietal region with gas locules and obliteration of sulci and gyri, without definite evidence of abscess formation (Fig. ). Contrast enhanced MRI scan of the brain demonstrated a subdural collection in the right fronto-temporo-parietal region with possible abscess formation in the right parietal region (Fig. ). Seizures were treated with oral sodium valproate and phenytoin sodium. He was referred for neurosurgical opinion, and the subdural collection was managed conservatively. Results of the indirect hemagglutination assay (IHA) for melioidosis antibodies were received on the following day; an antibody titre of more than 1/10,240 was strongly suggestive of an acute infection with Burkhoderia pseudomallei and a diagnosis of cerebral melioidosis was made.\nAntibiotics were changed to intravenous meropenem and oral trimethoprim/sulfamethoxazole (Co-trimoxazole/TMP-SMX). Initial intensive therapy with these antibiotics was continued for 8 weeks, until clinical improvement was evident with resolution of inflammatory markers and radiological improvement confirmed by repeat MRI scan of the brain. (Fig. ) Repeat blood cultures were sterile after 2 weeks of treatment with antibiotics. There were no further seizures, and the fever and the neurological symptoms resolved completely. He was discharged home with oral TMP-SMX and doxycycline, which were continued for 6 months, and the antiepileptics were gradually tailed off. At 6 months follow up he was asymptomatic. (Fig. ).

In February 2006, a previously healthy 58-year-old Sinhalese woman presented to our hospital with a history of intermittent fever, headache, loss of appetite, loss of weight, dry cough, and arthralgia of 5 weeks’ duration. She had no known past medical conditions or any family history of chronic disorders or similar illnesses. She was a housewife who frequently engaged in gardening and had no history of visits to forest areas or working in paddy fields. She was not alcoholic and was a nonsmoker.\nAt the beginning, she had been hospitalized, had undergone investigations, and had received broad-spectrum antibiotics. Due to the nature of the protracted illness with fever, and because she had an erythrocyte sedimentation rate (ESR) above 100 mm/h and increased C-reactive protein (CRP), a course of antituberculous antibiotics had been given over 2 weeks without definitive confirmation of the diagnosis of tuberculosis. While on antituberculous medications, instead of clinical improvement, she showed further deterioration of her illness and developed new problems, including appearance of a tender lump over the right temporal area over the course of 1 week and another similar lump over the anterior aspect of the left thigh of 5 days’ duration. At this juncture, she left the first hospital at her own wish and secured admission to Teaching Hospital Peradeniya (THP).\nOn admission to THP, she looked very ill and feeble and was febrile and tachypneic. She had a tender lump resembling an abscess over the right temporal area. Furthermore, she had similar lumps over the anterior aspect of the left thigh. She had an inflamed, swollen knee and wrist joints with a tender erythematous rash over both shins that resembled erythema nodosum. Her pulse rate was 110 beats/min with blood pressure of 100/65 mmHg. The results of her respiratory system and abdominal examinations were clinically normal. She was conscious, rational, and had no neck stiffness, with a clinically normal neurological examination result.\nBlood samples were taken for basic investigations and culture at this juncture. Diagnostic needle aspirates from the cystic lumps and knee joint effusions were purulent and were sent for bacteriological investigations. Blood samples for cultures were taken under aseptic conditions. Three separate blood cultures were taken in 30-minutes intervals and drawn into standard blood culture bottles. Knee joint and skin lump aspirates also were drawn into separate culture bottles under aseptic conditions. All the samples were transported to the microbiology laboratory, which is located within the hospital premises, and the cultures were done by a consultant microbiologist. Pending investigations, the patient was treated with intravenous (IV) co-amoxiclav (amoxicillin mixed with clavulanic acid).\nOn the fifth day of the patient’s admission, she became drowsy and developed focal seizures involving the right upper and lower limbs and lasting for around 2 minutes. She became drowsy with a Glasgow Coma Scale (GCS) score of 12/15. She moved all her limbs, and her deep tendon reflexes were normal, but she had an upgoing plantar response. She had no neck stiffness, positive Kernig sign, or focal neurological signs. She had persistent tachycardia with low blood pressure of 90/50 mmHg. Her respiratory rate was 30 breaths/min, and she had bibasal crepitations. She had bilateral knee joint effusions, and her knee joints were swollen, warm, erythematous, and tender. A tentative diagnosis of cerebral abscesses was made, and the patient was transferred to the intensive care unit.\nUrgent contrast-enhanced computed tomography of the brain showed a well-defined cystic mass in the right temporal region outside the skull vault and contrast-enhanced changes in the adjacent brain matter. Furthermore, a 12-lead electroencephalogram (EEG) showed a theta-wave focus over the right temporal area with intermittent epileptiform discharges compatible with structural brain damage. The results of her ultrasound examination of the abdomen and an echocardiogram were normal. Her white blood cell count was 3.3 × 109/L with neutrophils of 83% and lymphocytes of 12%. Her ESR was 120 mm/first hour, and her CRP level was 192 mg/L. Her chest x-ray showed multiple peripherally located, ill-defined cystic areas in both lung fields, more in the lung bases, suggestive of multiple lung abscesses. By that time, the blood culture, knee joint aspirate, and skin lump aspirates grew B. pseudomallei, which was confirmed by the local microbiologists with the help of international reference laboratories []. Thus, a diagnosis of melioidosis was confirmed, and treatment commenced.\nFollowing the confirmed diagnosis her antibiotic regimen was changed and started on IV meropenem 1 g 8-hourly for 8 days and later changed to IV imipenem 500 mg 6-hourly, based on the antibiotic sensitivity pattern of the bacterial isolate. Two more antibiotics were added to the regimen at the same time: IV ciprofloxacin 400 mg 12-hourly and IV ceftazidime 2 g 6-hourly. The patient showed gradual improvement of her general condition, and her fever subsided in a few days. However, all three antibiotics were continued for 30 days and changed to an oral antibiotic course comprising cotrimoxazole 1920 mg twice daily plus doxycycline 100 mg twice daily for 20 more weeks. Her seizures were controlled with sodium valproate 200 mg thrice daily. In follow-up, the patient’s chest x-ray, ESR (50 mm/h), CRP (0.7 mg/dl), and liver and renal profiles showed gradual improvement, and the results of her retroviral screening were negative. Her blood sugar and hemoglobin A1c levels were within normal limits. The result of repeat EEG in 3 months’ time was normal, and the patient’s sodium valproate was gradually tapered. After 6 months of antibiotic treatment, her ESR was 12 mm/first hour; her CRP was < 6 mg/L; and all of her other biochemical parameters were normal. Then, she was advised to come back to our hospital for annual screening to check for recurrence of the disease, including ESR and CRP measurement. She has had no recurrence of her illness during the last 13 years and remains well.\nSubsequently, how she contracted the infection was inquired about. She was able to recall contact with soil a few days prior to developing her illness. The footpath leading to her home had a side drain that was filled with mud and soil. She found that a worker had dug up the drain and piled mud and soil on the footpath. The patient, dismantled the piled-up soil with her bare feet and made the footpath accessible.

Write a detailed clinical case vignette based on the following key phrases: Infectious diseases, Bacterial infections, Rare diseases

A 42-year-old Sri Lankan man presented to the Colombo North Teaching Hospital, Ragama, Sri Lanka (CNTH) with a febrile illness of 6 days, accompanied by headache and constitutional symptoms. He was a grocer from Minuwangoda, a suburban area in the Western Province situated 44 km from Colombo. He was initially investigated and treated at a regional hospital for 4 days, and was transferred to the CNTH for specialized care. He gave a history of type 2 diabetes mellitus for 5 years without microvascular or macrovascular complications, and was a nonsmoker and a teetotaler. There were no specific symptoms suggesting a source of infection such as cough, abdominal pain, urinary symptoms, etc. He was febrile with a temperature of 39.10 C, and examination of the heart, lungs and abdomen was unremarkable. There was no papilloedema, focal neurological signs, pyramidal signs or neck stiffness. Initial laboratory work up revealed features of a bacterial infection, with neutrophil leukocytosis and elevated inflammatory markers (erythrocyte sedimentation rate – 101 mm/1st hour, C-reactive protein - 220 mg/dl). Initial blood cultures done at the regional hospital had yielded an isolate, which was reported as a Pseudomonas species; this was sensitive to ceftazidime, imipenem and meropenem and resistant to gentamicin and ceftriaxone. Other basic laboratory investigations including renal and liver function tests, electrolyte panel and urinalysis were normal. Chest x-ray and ultrasound scan of the abdomen were normal, and the trans-thoracic 2-D echo did not show any vegetations. As the unusual antibiotic sensitivity pattern suggested the possibility of melioidosis, blood was sent for serological testing to a specialized Melioidosis Research Laboratory at the Faculty of Medicine, University of Colombo.\nHe had been initially treated with intravenous ceftriaxone, and later with ceftazidime according to the antibiotic sensitivity pattern. Although the frequency and intensity of fever spikes reduced with treatment, he continued to have low grade fever and complain of anorexia, malaise and lethargy. On the 4th day after admission to the CNTH (day 10 of the illness), he developed simple partial seizures involving the left lower limb, progressing to persistent numbness of the left side of the body. An urgent CT scan of the head revealed a subdural collection over the right fronto-parietal region with gas locules and obliteration of sulci and gyri, without definite evidence of abscess formation (Fig. ). Contrast enhanced MRI scan of the brain demonstrated a subdural collection in the right fronto-temporo-parietal region with possible abscess formation in the right parietal region (Fig. ). Seizures were treated with oral sodium valproate and phenytoin sodium. He was referred for neurosurgical opinion, and the subdural collection was managed conservatively. Results of the indirect hemagglutination assay (IHA) for melioidosis antibodies were received on the following day; an antibody titre of more than 1/10,240 was strongly suggestive of an acute infection with Burkhoderia pseudomallei and a diagnosis of cerebral melioidosis was made.\nAntibiotics were changed to intravenous meropenem and oral trimethoprim/sulfamethoxazole (Co-trimoxazole/TMP-SMX). Initial intensive therapy with these antibiotics was continued for 8 weeks, until clinical improvement was evident with resolution of inflammatory markers and radiological improvement confirmed by repeat MRI scan of the brain. (Fig. ) Repeat blood cultures were sterile after 2 weeks of treatment with antibiotics. There were no further seizures, and the fever and the neurological symptoms resolved completely. He was discharged home with oral TMP-SMX and doxycycline, which were continued for 6 months, and the antiepileptics were gradually tailed off. At 6 months follow up he was asymptomatic. (Fig. ).

A 32-year-old male with a history of B. cenocepacia and Burkholderia multivorans developed an erythematous rash on the lower legs associated with an infective exacerbation of his chest. The rash resolved leaving grey discolouration but would occasionally flare up in the summer months. The biopsy showed features of capillaritis, and he was managed with topical steroids and compression hosiery.

Write a detailed clinical case vignette based on the following key phrases: Infectious diseases, Bacterial infections, Rare diseases

A 42-year-old Sri Lankan man presented to the Colombo North Teaching Hospital, Ragama, Sri Lanka (CNTH) with a febrile illness of 6 days, accompanied by headache and constitutional symptoms. He was a grocer from Minuwangoda, a suburban area in the Western Province situated 44 km from Colombo. He was initially investigated and treated at a regional hospital for 4 days, and was transferred to the CNTH for specialized care. He gave a history of type 2 diabetes mellitus for 5 years without microvascular or macrovascular complications, and was a nonsmoker and a teetotaler. There were no specific symptoms suggesting a source of infection such as cough, abdominal pain, urinary symptoms, etc. He was febrile with a temperature of 39.10 C, and examination of the heart, lungs and abdomen was unremarkable. There was no papilloedema, focal neurological signs, pyramidal signs or neck stiffness. Initial laboratory work up revealed features of a bacterial infection, with neutrophil leukocytosis and elevated inflammatory markers (erythrocyte sedimentation rate – 101 mm/1st hour, C-reactive protein - 220 mg/dl). Initial blood cultures done at the regional hospital had yielded an isolate, which was reported as a Pseudomonas species; this was sensitive to ceftazidime, imipenem and meropenem and resistant to gentamicin and ceftriaxone. Other basic laboratory investigations including renal and liver function tests, electrolyte panel and urinalysis were normal. Chest x-ray and ultrasound scan of the abdomen were normal, and the trans-thoracic 2-D echo did not show any vegetations. As the unusual antibiotic sensitivity pattern suggested the possibility of melioidosis, blood was sent for serological testing to a specialized Melioidosis Research Laboratory at the Faculty of Medicine, University of Colombo.\nHe had been initially treated with intravenous ceftriaxone, and later with ceftazidime according to the antibiotic sensitivity pattern. Although the frequency and intensity of fever spikes reduced with treatment, he continued to have low grade fever and complain of anorexia, malaise and lethargy. On the 4th day after admission to the CNTH (day 10 of the illness), he developed simple partial seizures involving the left lower limb, progressing to persistent numbness of the left side of the body. An urgent CT scan of the head revealed a subdural collection over the right fronto-parietal region with gas locules and obliteration of sulci and gyri, without definite evidence of abscess formation (Fig. ). Contrast enhanced MRI scan of the brain demonstrated a subdural collection in the right fronto-temporo-parietal region with possible abscess formation in the right parietal region (Fig. ). Seizures were treated with oral sodium valproate and phenytoin sodium. He was referred for neurosurgical opinion, and the subdural collection was managed conservatively. Results of the indirect hemagglutination assay (IHA) for melioidosis antibodies were received on the following day; an antibody titre of more than 1/10,240 was strongly suggestive of an acute infection with Burkhoderia pseudomallei and a diagnosis of cerebral melioidosis was made.\nAntibiotics were changed to intravenous meropenem and oral trimethoprim/sulfamethoxazole (Co-trimoxazole/TMP-SMX). Initial intensive therapy with these antibiotics was continued for 8 weeks, until clinical improvement was evident with resolution of inflammatory markers and radiological improvement confirmed by repeat MRI scan of the brain. (Fig. ) Repeat blood cultures were sterile after 2 weeks of treatment with antibiotics. There were no further seizures, and the fever and the neurological symptoms resolved completely. He was discharged home with oral TMP-SMX and doxycycline, which were continued for 6 months, and the antiepileptics were gradually tailed off. At 6 months follow up he was asymptomatic. (Fig. ).

A 23-year-old female with B. cenocepacia developed an erythematous maculopapular rash on the lower legs with associated arthropathy of her finger joints. This was clinically felt to be reactive leucocytoclastic vaculitis and a biopsy was not conducted. The vasculitis did not respond initially to oral prednisolone, and she was then commenced on azathioprine and the rash responded to this. Two years later, she died following a severe infective exacerbation of her chest.

Write a detailed clinical case vignette based on the following key phrases: Infectious diseases, Bacterial infections, Rare diseases

A 42-year-old Sri Lankan man presented to the Colombo North Teaching Hospital, Ragama, Sri Lanka (CNTH) with a febrile illness of 6 days, accompanied by headache and constitutional symptoms. He was a grocer from Minuwangoda, a suburban area in the Western Province situated 44 km from Colombo. He was initially investigated and treated at a regional hospital for 4 days, and was transferred to the CNTH for specialized care. He gave a history of type 2 diabetes mellitus for 5 years without microvascular or macrovascular complications, and was a nonsmoker and a teetotaler. There were no specific symptoms suggesting a source of infection such as cough, abdominal pain, urinary symptoms, etc. He was febrile with a temperature of 39.10 C, and examination of the heart, lungs and abdomen was unremarkable. There was no papilloedema, focal neurological signs, pyramidal signs or neck stiffness. Initial laboratory work up revealed features of a bacterial infection, with neutrophil leukocytosis and elevated inflammatory markers (erythrocyte sedimentation rate – 101 mm/1st hour, C-reactive protein - 220 mg/dl). Initial blood cultures done at the regional hospital had yielded an isolate, which was reported as a Pseudomonas species; this was sensitive to ceftazidime, imipenem and meropenem and resistant to gentamicin and ceftriaxone. Other basic laboratory investigations including renal and liver function tests, electrolyte panel and urinalysis were normal. Chest x-ray and ultrasound scan of the abdomen were normal, and the trans-thoracic 2-D echo did not show any vegetations. As the unusual antibiotic sensitivity pattern suggested the possibility of melioidosis, blood was sent for serological testing to a specialized Melioidosis Research Laboratory at the Faculty of Medicine, University of Colombo.\nHe had been initially treated with intravenous ceftriaxone, and later with ceftazidime according to the antibiotic sensitivity pattern. Although the frequency and intensity of fever spikes reduced with treatment, he continued to have low grade fever and complain of anorexia, malaise and lethargy. On the 4th day after admission to the CNTH (day 10 of the illness), he developed simple partial seizures involving the left lower limb, progressing to persistent numbness of the left side of the body. An urgent CT scan of the head revealed a subdural collection over the right fronto-parietal region with gas locules and obliteration of sulci and gyri, without definite evidence of abscess formation (Fig. ). Contrast enhanced MRI scan of the brain demonstrated a subdural collection in the right fronto-temporo-parietal region with possible abscess formation in the right parietal region (Fig. ). Seizures were treated with oral sodium valproate and phenytoin sodium. He was referred for neurosurgical opinion, and the subdural collection was managed conservatively. Results of the indirect hemagglutination assay (IHA) for melioidosis antibodies were received on the following day; an antibody titre of more than 1/10,240 was strongly suggestive of an acute infection with Burkhoderia pseudomallei and a diagnosis of cerebral melioidosis was made.\nAntibiotics were changed to intravenous meropenem and oral trimethoprim/sulfamethoxazole (Co-trimoxazole/TMP-SMX). Initial intensive therapy with these antibiotics was continued for 8 weeks, until clinical improvement was evident with resolution of inflammatory markers and radiological improvement confirmed by repeat MRI scan of the brain. (Fig. ) Repeat blood cultures were sterile after 2 weeks of treatment with antibiotics. There were no further seizures, and the fever and the neurological symptoms resolved completely. He was discharged home with oral TMP-SMX and doxycycline, which were continued for 6 months, and the antiepileptics were gradually tailed off. At 6 months follow up he was asymptomatic. (Fig. ).

A 42 year old diabetic woman from North Western Province of Sri Lanka presented with abdominal pain, vomiting and intermittent fever for one month. She had recurrent skin abscesses 6 months before presentation which was treated with incision and drainage and a short course of antibiotics for which there was only partial improvement. Three months before presentation to us she was found to have multiple liver abscesses which were aspirated in a local hospital. The aspirate grew “coliforms” resistant to gentamicin and sensitive to ceftazidime. She was treated with cefuroxime, meropenem, co-amoxyclav and metronidazole; further identification of the organism was not done at the local hospital.\nOn presentation to us she had high fever and tender hepatomegaly. Her body weight was 40 kg. Rest of the examination including nervous system was normal.\nHer full blood count showed leukocytosis [15.7×109/L] and granulocytosis [11.3 × 109/L], ESR was 100 mm in the 1st hour and C-reactive protein was 98.4 mg/L. Ultra sound scan of abdomen showed multiple liver and splenic abscesses.\nPresence of recurrent multiple liver and splenic abscesses in a diabetic patient who had recurrent skin abscess in the past made us consider melioidosis in the differential diagnosis. Intravenous meropenem 2g eight hourly was started empirically and aspirate was sent with a sample of serum to Faculty of Medicine, University of Colombo which serves as the National Reference Laboratory, to confirm the diagnosis. There the aspirate yielded pinpoint colonies on blood, chocolate and Macconkey agar after overnight incubation. Since biochemical panels are not very accurate in diagnosis of Burkholderia pseudomallei, isolate was subjected to PCR which confirmed the diagnosis.\nSerum antibodies to melioidin antigen using an in-house indirect haemagglutination (IHA) test based on that described by Alexander et al. with antigen prepared from local strains of B.pseudomallei [] were positive at a titre of 1:10240.\nAfter confirmation of melioidosis intravenous meropenem was continued. However after a week of treatment the disease course was complicated by bilateral lower limb weakness which progressed over the next 4 days. Her lower limbs were flaccid and deep tendon reflexes were absent. There was no sensory sign or bladder/bowel involvement. Cerebro-spinal fluid analysis showed protein of 114.5 mg/dl, glucose 62 mg/dl, white cells <10 mm9/L and red cells < 10 mm9/L. MRI scan of the brain was normal. The nerve conduction study showed evidence of severe peripheral neuropathy with axonal degeneration; compatible with a primary axonal type inflammatory neuropathy such as acute motor axonal neuropathy or acute sensory motor axonal neuropathy.\nA diagnosis of Guillan-Barre syndrome was made based on Brighton case definition (Table ) () and she was treated with 4 cycles of plasmapharesis on alternate days for which there was marked improvement of neurological deficit.\nWith intravenous meropenem patient further improved and her ESR and CRP became normal. Repeat ultrasound scan of abdomen showed reduction of the size of liver and splenic abscesses.\nEradication therapy with cotrimoxazole 1920 mg 12 hourly and co-amoxyclav 625 mg 8 hourly was started on the seventh week and overlapped with intravenous antibiotic for further two weeks. Patient was discharged to outpatient clinic after two weeks of oral antibiotics with a plan to continue them for12 weeks. At the end of 12 weeks she had no residual neurological weakness and there was no sign of a relapse.

Write a detailed clinical case vignette based on the following key phrases: Infectious diseases, Bacterial infections, Rare diseases

In February 2006, a previously healthy 58-year-old Sinhalese woman presented to our hospital with a history of intermittent fever, headache, loss of appetite, loss of weight, dry cough, and arthralgia of 5 weeks’ duration. She had no known past medical conditions or any family history of chronic disorders or similar illnesses. She was a housewife who frequently engaged in gardening and had no history of visits to forest areas or working in paddy fields. She was not alcoholic and was a nonsmoker.\nAt the beginning, she had been hospitalized, had undergone investigations, and had received broad-spectrum antibiotics. Due to the nature of the protracted illness with fever, and because she had an erythrocyte sedimentation rate (ESR) above 100 mm/h and increased C-reactive protein (CRP), a course of antituberculous antibiotics had been given over 2 weeks without definitive confirmation of the diagnosis of tuberculosis. While on antituberculous medications, instead of clinical improvement, she showed further deterioration of her illness and developed new problems, including appearance of a tender lump over the right temporal area over the course of 1 week and another similar lump over the anterior aspect of the left thigh of 5 days’ duration. At this juncture, she left the first hospital at her own wish and secured admission to Teaching Hospital Peradeniya (THP).\nOn admission to THP, she looked very ill and feeble and was febrile and tachypneic. She had a tender lump resembling an abscess over the right temporal area. Furthermore, she had similar lumps over the anterior aspect of the left thigh. She had an inflamed, swollen knee and wrist joints with a tender erythematous rash over both shins that resembled erythema nodosum. Her pulse rate was 110 beats/min with blood pressure of 100/65 mmHg. The results of her respiratory system and abdominal examinations were clinically normal. She was conscious, rational, and had no neck stiffness, with a clinically normal neurological examination result.\nBlood samples were taken for basic investigations and culture at this juncture. Diagnostic needle aspirates from the cystic lumps and knee joint effusions were purulent and were sent for bacteriological investigations. Blood samples for cultures were taken under aseptic conditions. Three separate blood cultures were taken in 30-minutes intervals and drawn into standard blood culture bottles. Knee joint and skin lump aspirates also were drawn into separate culture bottles under aseptic conditions. All the samples were transported to the microbiology laboratory, which is located within the hospital premises, and the cultures were done by a consultant microbiologist. Pending investigations, the patient was treated with intravenous (IV) co-amoxiclav (amoxicillin mixed with clavulanic acid).\nOn the fifth day of the patient’s admission, she became drowsy and developed focal seizures involving the right upper and lower limbs and lasting for around 2 minutes. She became drowsy with a Glasgow Coma Scale (GCS) score of 12/15. She moved all her limbs, and her deep tendon reflexes were normal, but she had an upgoing plantar response. She had no neck stiffness, positive Kernig sign, or focal neurological signs. She had persistent tachycardia with low blood pressure of 90/50 mmHg. Her respiratory rate was 30 breaths/min, and she had bibasal crepitations. She had bilateral knee joint effusions, and her knee joints were swollen, warm, erythematous, and tender. A tentative diagnosis of cerebral abscesses was made, and the patient was transferred to the intensive care unit.\nUrgent contrast-enhanced computed tomography of the brain showed a well-defined cystic mass in the right temporal region outside the skull vault and contrast-enhanced changes in the adjacent brain matter. Furthermore, a 12-lead electroencephalogram (EEG) showed a theta-wave focus over the right temporal area with intermittent epileptiform discharges compatible with structural brain damage. The results of her ultrasound examination of the abdomen and an echocardiogram were normal. Her white blood cell count was 3.3 × 109/L with neutrophils of 83% and lymphocytes of 12%. Her ESR was 120 mm/first hour, and her CRP level was 192 mg/L. Her chest x-ray showed multiple peripherally located, ill-defined cystic areas in both lung fields, more in the lung bases, suggestive of multiple lung abscesses. By that time, the blood culture, knee joint aspirate, and skin lump aspirates grew B. pseudomallei, which was confirmed by the local microbiologists with the help of international reference laboratories []. Thus, a diagnosis of melioidosis was confirmed, and treatment commenced.\nFollowing the confirmed diagnosis her antibiotic regimen was changed and started on IV meropenem 1 g 8-hourly for 8 days and later changed to IV imipenem 500 mg 6-hourly, based on the antibiotic sensitivity pattern of the bacterial isolate. Two more antibiotics were added to the regimen at the same time: IV ciprofloxacin 400 mg 12-hourly and IV ceftazidime 2 g 6-hourly. The patient showed gradual improvement of her general condition, and her fever subsided in a few days. However, all three antibiotics were continued for 30 days and changed to an oral antibiotic course comprising cotrimoxazole 1920 mg twice daily plus doxycycline 100 mg twice daily for 20 more weeks. Her seizures were controlled with sodium valproate 200 mg thrice daily. In follow-up, the patient’s chest x-ray, ESR (50 mm/h), CRP (0.7 mg/dl), and liver and renal profiles showed gradual improvement, and the results of her retroviral screening were negative. Her blood sugar and hemoglobin A1c levels were within normal limits. The result of repeat EEG in 3 months’ time was normal, and the patient’s sodium valproate was gradually tapered. After 6 months of antibiotic treatment, her ESR was 12 mm/first hour; her CRP was < 6 mg/L; and all of her other biochemical parameters were normal. Then, she was advised to come back to our hospital for annual screening to check for recurrence of the disease, including ESR and CRP measurement. She has had no recurrence of her illness during the last 13 years and remains well.\nSubsequently, how she contracted the infection was inquired about. She was able to recall contact with soil a few days prior to developing her illness. The footpath leading to her home had a side drain that was filled with mud and soil. She found that a worker had dug up the drain and piled mud and soil on the footpath. The patient, dismantled the piled-up soil with her bare feet and made the footpath accessible.

A 32-year-old male with a history of B. cenocepacia and Burkholderia multivorans developed an erythematous rash on the lower legs associated with an infective exacerbation of his chest. The rash resolved leaving grey discolouration but would occasionally flare up in the summer months. The biopsy showed features of capillaritis, and he was managed with topical steroids and compression hosiery.

Write a detailed clinical case vignette based on the following key phrases: Infectious diseases, Bacterial infections, Rare diseases

In February 2006, a previously healthy 58-year-old Sinhalese woman presented to our hospital with a history of intermittent fever, headache, loss of appetite, loss of weight, dry cough, and arthralgia of 5 weeks’ duration. She had no known past medical conditions or any family history of chronic disorders or similar illnesses. She was a housewife who frequently engaged in gardening and had no history of visits to forest areas or working in paddy fields. She was not alcoholic and was a nonsmoker.\nAt the beginning, she had been hospitalized, had undergone investigations, and had received broad-spectrum antibiotics. Due to the nature of the protracted illness with fever, and because she had an erythrocyte sedimentation rate (ESR) above 100 mm/h and increased C-reactive protein (CRP), a course of antituberculous antibiotics had been given over 2 weeks without definitive confirmation of the diagnosis of tuberculosis. While on antituberculous medications, instead of clinical improvement, she showed further deterioration of her illness and developed new problems, including appearance of a tender lump over the right temporal area over the course of 1 week and another similar lump over the anterior aspect of the left thigh of 5 days’ duration. At this juncture, she left the first hospital at her own wish and secured admission to Teaching Hospital Peradeniya (THP).\nOn admission to THP, she looked very ill and feeble and was febrile and tachypneic. She had a tender lump resembling an abscess over the right temporal area. Furthermore, she had similar lumps over the anterior aspect of the left thigh. She had an inflamed, swollen knee and wrist joints with a tender erythematous rash over both shins that resembled erythema nodosum. Her pulse rate was 110 beats/min with blood pressure of 100/65 mmHg. The results of her respiratory system and abdominal examinations were clinically normal. She was conscious, rational, and had no neck stiffness, with a clinically normal neurological examination result.\nBlood samples were taken for basic investigations and culture at this juncture. Diagnostic needle aspirates from the cystic lumps and knee joint effusions were purulent and were sent for bacteriological investigations. Blood samples for cultures were taken under aseptic conditions. Three separate blood cultures were taken in 30-minutes intervals and drawn into standard blood culture bottles. Knee joint and skin lump aspirates also were drawn into separate culture bottles under aseptic conditions. All the samples were transported to the microbiology laboratory, which is located within the hospital premises, and the cultures were done by a consultant microbiologist. Pending investigations, the patient was treated with intravenous (IV) co-amoxiclav (amoxicillin mixed with clavulanic acid).\nOn the fifth day of the patient’s admission, she became drowsy and developed focal seizures involving the right upper and lower limbs and lasting for around 2 minutes. She became drowsy with a Glasgow Coma Scale (GCS) score of 12/15. She moved all her limbs, and her deep tendon reflexes were normal, but she had an upgoing plantar response. She had no neck stiffness, positive Kernig sign, or focal neurological signs. She had persistent tachycardia with low blood pressure of 90/50 mmHg. Her respiratory rate was 30 breaths/min, and she had bibasal crepitations. She had bilateral knee joint effusions, and her knee joints were swollen, warm, erythematous, and tender. A tentative diagnosis of cerebral abscesses was made, and the patient was transferred to the intensive care unit.\nUrgent contrast-enhanced computed tomography of the brain showed a well-defined cystic mass in the right temporal region outside the skull vault and contrast-enhanced changes in the adjacent brain matter. Furthermore, a 12-lead electroencephalogram (EEG) showed a theta-wave focus over the right temporal area with intermittent epileptiform discharges compatible with structural brain damage. The results of her ultrasound examination of the abdomen and an echocardiogram were normal. Her white blood cell count was 3.3 × 109/L with neutrophils of 83% and lymphocytes of 12%. Her ESR was 120 mm/first hour, and her CRP level was 192 mg/L. Her chest x-ray showed multiple peripherally located, ill-defined cystic areas in both lung fields, more in the lung bases, suggestive of multiple lung abscesses. By that time, the blood culture, knee joint aspirate, and skin lump aspirates grew B. pseudomallei, which was confirmed by the local microbiologists with the help of international reference laboratories []. Thus, a diagnosis of melioidosis was confirmed, and treatment commenced.\nFollowing the confirmed diagnosis her antibiotic regimen was changed and started on IV meropenem 1 g 8-hourly for 8 days and later changed to IV imipenem 500 mg 6-hourly, based on the antibiotic sensitivity pattern of the bacterial isolate. Two more antibiotics were added to the regimen at the same time: IV ciprofloxacin 400 mg 12-hourly and IV ceftazidime 2 g 6-hourly. The patient showed gradual improvement of her general condition, and her fever subsided in a few days. However, all three antibiotics were continued for 30 days and changed to an oral antibiotic course comprising cotrimoxazole 1920 mg twice daily plus doxycycline 100 mg twice daily for 20 more weeks. Her seizures were controlled with sodium valproate 200 mg thrice daily. In follow-up, the patient’s chest x-ray, ESR (50 mm/h), CRP (0.7 mg/dl), and liver and renal profiles showed gradual improvement, and the results of her retroviral screening were negative. Her blood sugar and hemoglobin A1c levels were within normal limits. The result of repeat EEG in 3 months’ time was normal, and the patient’s sodium valproate was gradually tapered. After 6 months of antibiotic treatment, her ESR was 12 mm/first hour; her CRP was < 6 mg/L; and all of her other biochemical parameters were normal. Then, she was advised to come back to our hospital for annual screening to check for recurrence of the disease, including ESR and CRP measurement. She has had no recurrence of her illness during the last 13 years and remains well.\nSubsequently, how she contracted the infection was inquired about. She was able to recall contact with soil a few days prior to developing her illness. The footpath leading to her home had a side drain that was filled with mud and soil. She found that a worker had dug up the drain and piled mud and soil on the footpath. The patient, dismantled the piled-up soil with her bare feet and made the footpath accessible.

A 23-year-old female with B. cenocepacia developed an erythematous maculopapular rash on the lower legs with associated arthropathy of her finger joints. This was clinically felt to be reactive leucocytoclastic vaculitis and a biopsy was not conducted. The vasculitis did not respond initially to oral prednisolone, and she was then commenced on azathioprine and the rash responded to this. Two years later, she died following a severe infective exacerbation of her chest.

Write a detailed clinical case vignette based on the following key phrases: Infectious diseases, Bacterial infections, Rare diseases

In February 2006, a previously healthy 58-year-old Sinhalese woman presented to our hospital with a history of intermittent fever, headache, loss of appetite, loss of weight, dry cough, and arthralgia of 5 weeks’ duration. She had no known past medical conditions or any family history of chronic disorders or similar illnesses. She was a housewife who frequently engaged in gardening and had no history of visits to forest areas or working in paddy fields. She was not alcoholic and was a nonsmoker.\nAt the beginning, she had been hospitalized, had undergone investigations, and had received broad-spectrum antibiotics. Due to the nature of the protracted illness with fever, and because she had an erythrocyte sedimentation rate (ESR) above 100 mm/h and increased C-reactive protein (CRP), a course of antituberculous antibiotics had been given over 2 weeks without definitive confirmation of the diagnosis of tuberculosis. While on antituberculous medications, instead of clinical improvement, she showed further deterioration of her illness and developed new problems, including appearance of a tender lump over the right temporal area over the course of 1 week and another similar lump over the anterior aspect of the left thigh of 5 days’ duration. At this juncture, she left the first hospital at her own wish and secured admission to Teaching Hospital Peradeniya (THP).\nOn admission to THP, she looked very ill and feeble and was febrile and tachypneic. She had a tender lump resembling an abscess over the right temporal area. Furthermore, she had similar lumps over the anterior aspect of the left thigh. She had an inflamed, swollen knee and wrist joints with a tender erythematous rash over both shins that resembled erythema nodosum. Her pulse rate was 110 beats/min with blood pressure of 100/65 mmHg. The results of her respiratory system and abdominal examinations were clinically normal. She was conscious, rational, and had no neck stiffness, with a clinically normal neurological examination result.\nBlood samples were taken for basic investigations and culture at this juncture. Diagnostic needle aspirates from the cystic lumps and knee joint effusions were purulent and were sent for bacteriological investigations. Blood samples for cultures were taken under aseptic conditions. Three separate blood cultures were taken in 30-minutes intervals and drawn into standard blood culture bottles. Knee joint and skin lump aspirates also were drawn into separate culture bottles under aseptic conditions. All the samples were transported to the microbiology laboratory, which is located within the hospital premises, and the cultures were done by a consultant microbiologist. Pending investigations, the patient was treated with intravenous (IV) co-amoxiclav (amoxicillin mixed with clavulanic acid).\nOn the fifth day of the patient’s admission, she became drowsy and developed focal seizures involving the right upper and lower limbs and lasting for around 2 minutes. She became drowsy with a Glasgow Coma Scale (GCS) score of 12/15. She moved all her limbs, and her deep tendon reflexes were normal, but she had an upgoing plantar response. She had no neck stiffness, positive Kernig sign, or focal neurological signs. She had persistent tachycardia with low blood pressure of 90/50 mmHg. Her respiratory rate was 30 breaths/min, and she had bibasal crepitations. She had bilateral knee joint effusions, and her knee joints were swollen, warm, erythematous, and tender. A tentative diagnosis of cerebral abscesses was made, and the patient was transferred to the intensive care unit.\nUrgent contrast-enhanced computed tomography of the brain showed a well-defined cystic mass in the right temporal region outside the skull vault and contrast-enhanced changes in the adjacent brain matter. Furthermore, a 12-lead electroencephalogram (EEG) showed a theta-wave focus over the right temporal area with intermittent epileptiform discharges compatible with structural brain damage. The results of her ultrasound examination of the abdomen and an echocardiogram were normal. Her white blood cell count was 3.3 × 109/L with neutrophils of 83% and lymphocytes of 12%. Her ESR was 120 mm/first hour, and her CRP level was 192 mg/L. Her chest x-ray showed multiple peripherally located, ill-defined cystic areas in both lung fields, more in the lung bases, suggestive of multiple lung abscesses. By that time, the blood culture, knee joint aspirate, and skin lump aspirates grew B. pseudomallei, which was confirmed by the local microbiologists with the help of international reference laboratories []. Thus, a diagnosis of melioidosis was confirmed, and treatment commenced.\nFollowing the confirmed diagnosis her antibiotic regimen was changed and started on IV meropenem 1 g 8-hourly for 8 days and later changed to IV imipenem 500 mg 6-hourly, based on the antibiotic sensitivity pattern of the bacterial isolate. Two more antibiotics were added to the regimen at the same time: IV ciprofloxacin 400 mg 12-hourly and IV ceftazidime 2 g 6-hourly. The patient showed gradual improvement of her general condition, and her fever subsided in a few days. However, all three antibiotics were continued for 30 days and changed to an oral antibiotic course comprising cotrimoxazole 1920 mg twice daily plus doxycycline 100 mg twice daily for 20 more weeks. Her seizures were controlled with sodium valproate 200 mg thrice daily. In follow-up, the patient’s chest x-ray, ESR (50 mm/h), CRP (0.7 mg/dl), and liver and renal profiles showed gradual improvement, and the results of her retroviral screening were negative. Her blood sugar and hemoglobin A1c levels were within normal limits. The result of repeat EEG in 3 months’ time was normal, and the patient’s sodium valproate was gradually tapered. After 6 months of antibiotic treatment, her ESR was 12 mm/first hour; her CRP was < 6 mg/L; and all of her other biochemical parameters were normal. Then, she was advised to come back to our hospital for annual screening to check for recurrence of the disease, including ESR and CRP measurement. She has had no recurrence of her illness during the last 13 years and remains well.\nSubsequently, how she contracted the infection was inquired about. She was able to recall contact with soil a few days prior to developing her illness. The footpath leading to her home had a side drain that was filled with mud and soil. She found that a worker had dug up the drain and piled mud and soil on the footpath. The patient, dismantled the piled-up soil with her bare feet and made the footpath accessible.

A 42 year old diabetic woman from North Western Province of Sri Lanka presented with abdominal pain, vomiting and intermittent fever for one month. She had recurrent skin abscesses 6 months before presentation which was treated with incision and drainage and a short course of antibiotics for which there was only partial improvement. Three months before presentation to us she was found to have multiple liver abscesses which were aspirated in a local hospital. The aspirate grew “coliforms” resistant to gentamicin and sensitive to ceftazidime. She was treated with cefuroxime, meropenem, co-amoxyclav and metronidazole; further identification of the organism was not done at the local hospital.\nOn presentation to us she had high fever and tender hepatomegaly. Her body weight was 40 kg. Rest of the examination including nervous system was normal.\nHer full blood count showed leukocytosis [15.7×109/L] and granulocytosis [11.3 × 109/L], ESR was 100 mm in the 1st hour and C-reactive protein was 98.4 mg/L. Ultra sound scan of abdomen showed multiple liver and splenic abscesses.\nPresence of recurrent multiple liver and splenic abscesses in a diabetic patient who had recurrent skin abscess in the past made us consider melioidosis in the differential diagnosis. Intravenous meropenem 2g eight hourly was started empirically and aspirate was sent with a sample of serum to Faculty of Medicine, University of Colombo which serves as the National Reference Laboratory, to confirm the diagnosis. There the aspirate yielded pinpoint colonies on blood, chocolate and Macconkey agar after overnight incubation. Since biochemical panels are not very accurate in diagnosis of Burkholderia pseudomallei, isolate was subjected to PCR which confirmed the diagnosis.\nSerum antibodies to melioidin antigen using an in-house indirect haemagglutination (IHA) test based on that described by Alexander et al. with antigen prepared from local strains of B.pseudomallei [] were positive at a titre of 1:10240.\nAfter confirmation of melioidosis intravenous meropenem was continued. However after a week of treatment the disease course was complicated by bilateral lower limb weakness which progressed over the next 4 days. Her lower limbs were flaccid and deep tendon reflexes were absent. There was no sensory sign or bladder/bowel involvement. Cerebro-spinal fluid analysis showed protein of 114.5 mg/dl, glucose 62 mg/dl, white cells <10 mm9/L and red cells < 10 mm9/L. MRI scan of the brain was normal. The nerve conduction study showed evidence of severe peripheral neuropathy with axonal degeneration; compatible with a primary axonal type inflammatory neuropathy such as acute motor axonal neuropathy or acute sensory motor axonal neuropathy.\nA diagnosis of Guillan-Barre syndrome was made based on Brighton case definition (Table ) () and she was treated with 4 cycles of plasmapharesis on alternate days for which there was marked improvement of neurological deficit.\nWith intravenous meropenem patient further improved and her ESR and CRP became normal. Repeat ultrasound scan of abdomen showed reduction of the size of liver and splenic abscesses.\nEradication therapy with cotrimoxazole 1920 mg 12 hourly and co-amoxyclav 625 mg 8 hourly was started on the seventh week and overlapped with intravenous antibiotic for further two weeks. Patient was discharged to outpatient clinic after two weeks of oral antibiotics with a plan to continue them for12 weeks. At the end of 12 weeks she had no residual neurological weakness and there was no sign of a relapse.

Write a detailed clinical case vignette based on the following key phrases: Infectious diseases, Bacterial infections, Rare diseases

A 32-year-old male with a history of B. cenocepacia and Burkholderia multivorans developed an erythematous rash on the lower legs associated with an infective exacerbation of his chest. The rash resolved leaving grey discolouration but would occasionally flare up in the summer months. The biopsy showed features of capillaritis, and he was managed with topical steroids and compression hosiery.

A 23-year-old female with B. cenocepacia developed an erythematous maculopapular rash on the lower legs with associated arthropathy of her finger joints. This was clinically felt to be reactive leucocytoclastic vaculitis and a biopsy was not conducted. The vasculitis did not respond initially to oral prednisolone, and she was then commenced on azathioprine and the rash responded to this. Two years later, she died following a severe infective exacerbation of her chest.

Write a detailed clinical case vignette based on the following key phrases: Infectious diseases, Bacterial infections, Rare diseases

A 42 year old diabetic woman from North Western Province of Sri Lanka presented with abdominal pain, vomiting and intermittent fever for one month. She had recurrent skin abscesses 6 months before presentation which was treated with incision and drainage and a short course of antibiotics for which there was only partial improvement. Three months before presentation to us she was found to have multiple liver abscesses which were aspirated in a local hospital. The aspirate grew “coliforms” resistant to gentamicin and sensitive to ceftazidime. She was treated with cefuroxime, meropenem, co-amoxyclav and metronidazole; further identification of the organism was not done at the local hospital.\nOn presentation to us she had high fever and tender hepatomegaly. Her body weight was 40 kg. Rest of the examination including nervous system was normal.\nHer full blood count showed leukocytosis [15.7×109/L] and granulocytosis [11.3 × 109/L], ESR was 100 mm in the 1st hour and C-reactive protein was 98.4 mg/L. Ultra sound scan of abdomen showed multiple liver and splenic abscesses.\nPresence of recurrent multiple liver and splenic abscesses in a diabetic patient who had recurrent skin abscess in the past made us consider melioidosis in the differential diagnosis. Intravenous meropenem 2g eight hourly was started empirically and aspirate was sent with a sample of serum to Faculty of Medicine, University of Colombo which serves as the National Reference Laboratory, to confirm the diagnosis. There the aspirate yielded pinpoint colonies on blood, chocolate and Macconkey agar after overnight incubation. Since biochemical panels are not very accurate in diagnosis of Burkholderia pseudomallei, isolate was subjected to PCR which confirmed the diagnosis.\nSerum antibodies to melioidin antigen using an in-house indirect haemagglutination (IHA) test based on that described by Alexander et al. with antigen prepared from local strains of B.pseudomallei [] were positive at a titre of 1:10240.\nAfter confirmation of melioidosis intravenous meropenem was continued. However after a week of treatment the disease course was complicated by bilateral lower limb weakness which progressed over the next 4 days. Her lower limbs were flaccid and deep tendon reflexes were absent. There was no sensory sign or bladder/bowel involvement. Cerebro-spinal fluid analysis showed protein of 114.5 mg/dl, glucose 62 mg/dl, white cells <10 mm9/L and red cells < 10 mm9/L. MRI scan of the brain was normal. The nerve conduction study showed evidence of severe peripheral neuropathy with axonal degeneration; compatible with a primary axonal type inflammatory neuropathy such as acute motor axonal neuropathy or acute sensory motor axonal neuropathy.\nA diagnosis of Guillan-Barre syndrome was made based on Brighton case definition (Table ) () and she was treated with 4 cycles of plasmapharesis on alternate days for which there was marked improvement of neurological deficit.\nWith intravenous meropenem patient further improved and her ESR and CRP became normal. Repeat ultrasound scan of abdomen showed reduction of the size of liver and splenic abscesses.\nEradication therapy with cotrimoxazole 1920 mg 12 hourly and co-amoxyclav 625 mg 8 hourly was started on the seventh week and overlapped with intravenous antibiotic for further two weeks. Patient was discharged to outpatient clinic after two weeks of oral antibiotics with a plan to continue them for12 weeks. At the end of 12 weeks she had no residual neurological weakness and there was no sign of a relapse.

A 32-year-old male with a history of B. cenocepacia and Burkholderia multivorans developed an erythematous rash on the lower legs associated with an infective exacerbation of his chest. The rash resolved leaving grey discolouration but would occasionally flare up in the summer months. The biopsy showed features of capillaritis, and he was managed with topical steroids and compression hosiery.

Write a detailed clinical case vignette based on the following key phrases: Infectious diseases, Bacterial infections, Rare diseases

A 42 year old diabetic woman from North Western Province of Sri Lanka presented with abdominal pain, vomiting and intermittent fever for one month. She had recurrent skin abscesses 6 months before presentation which was treated with incision and drainage and a short course of antibiotics for which there was only partial improvement. Three months before presentation to us she was found to have multiple liver abscesses which were aspirated in a local hospital. The aspirate grew “coliforms” resistant to gentamicin and sensitive to ceftazidime. She was treated with cefuroxime, meropenem, co-amoxyclav and metronidazole; further identification of the organism was not done at the local hospital.\nOn presentation to us she had high fever and tender hepatomegaly. Her body weight was 40 kg. Rest of the examination including nervous system was normal.\nHer full blood count showed leukocytosis [15.7×109/L] and granulocytosis [11.3 × 109/L], ESR was 100 mm in the 1st hour and C-reactive protein was 98.4 mg/L. Ultra sound scan of abdomen showed multiple liver and splenic abscesses.\nPresence of recurrent multiple liver and splenic abscesses in a diabetic patient who had recurrent skin abscess in the past made us consider melioidosis in the differential diagnosis. Intravenous meropenem 2g eight hourly was started empirically and aspirate was sent with a sample of serum to Faculty of Medicine, University of Colombo which serves as the National Reference Laboratory, to confirm the diagnosis. There the aspirate yielded pinpoint colonies on blood, chocolate and Macconkey agar after overnight incubation. Since biochemical panels are not very accurate in diagnosis of Burkholderia pseudomallei, isolate was subjected to PCR which confirmed the diagnosis.\nSerum antibodies to melioidin antigen using an in-house indirect haemagglutination (IHA) test based on that described by Alexander et al. with antigen prepared from local strains of B.pseudomallei [] were positive at a titre of 1:10240.\nAfter confirmation of melioidosis intravenous meropenem was continued. However after a week of treatment the disease course was complicated by bilateral lower limb weakness which progressed over the next 4 days. Her lower limbs were flaccid and deep tendon reflexes were absent. There was no sensory sign or bladder/bowel involvement. Cerebro-spinal fluid analysis showed protein of 114.5 mg/dl, glucose 62 mg/dl, white cells <10 mm9/L and red cells < 10 mm9/L. MRI scan of the brain was normal. The nerve conduction study showed evidence of severe peripheral neuropathy with axonal degeneration; compatible with a primary axonal type inflammatory neuropathy such as acute motor axonal neuropathy or acute sensory motor axonal neuropathy.\nA diagnosis of Guillan-Barre syndrome was made based on Brighton case definition (Table ) () and she was treated with 4 cycles of plasmapharesis on alternate days for which there was marked improvement of neurological deficit.\nWith intravenous meropenem patient further improved and her ESR and CRP became normal. Repeat ultrasound scan of abdomen showed reduction of the size of liver and splenic abscesses.\nEradication therapy with cotrimoxazole 1920 mg 12 hourly and co-amoxyclav 625 mg 8 hourly was started on the seventh week and overlapped with intravenous antibiotic for further two weeks. Patient was discharged to outpatient clinic after two weeks of oral antibiotics with a plan to continue them for12 weeks. At the end of 12 weeks she had no residual neurological weakness and there was no sign of a relapse.

A 23-year-old female with B. cenocepacia developed an erythematous maculopapular rash on the lower legs with associated arthropathy of her finger joints. This was clinically felt to be reactive leucocytoclastic vaculitis and a biopsy was not conducted. The vasculitis did not respond initially to oral prednisolone, and she was then commenced on azathioprine and the rash responded to this. Two years later, she died following a severe infective exacerbation of her chest.

Write a detailed clinical case vignette based on the following key phrases: Infectious diseases, Bacterial infections, Rare diseases

Patient 1. A 2-years-old female infant was referred to the First Affiliated Hospital, Jinan University, due to elevated serum total bile acids (TBA) discovered for 21 months. At the age 3 months, she was admitted to Women and Children's Hospital of Quanzhou because of jaundice for 2 months. Laboratory test revealed that the serum levels of TBA, direct bilirubin (DBIL), aspartate transaminase (AST) and alanine transaminase (ALT) were all elevated (Table ), and she was thus diagnosed to have cholestatic liver disease. After being treated with intravenous reduced glutathione and ademetionine-1,4-butanedisulfonate for 9 days, which were commonly used in cholestatic patients with elevated alanine transaminase levels, her jaundice was alleviated, but the liver function indices remained abnormal (Table ). Then oral ursodesoxycholic acid was given and she was discharged at the age 3.3 months. During the subsequent follow-up over 20 months, she showed normal anthropometric and neurobehavioral development without abnormal appearance, and her cholestasis resolved completely since the age 7 months. However, persistently raised TBA levels were observed on repeated biochemical analyses (Table ). So she was referred to our hospital for further investigation and management when aged 2 years.\nThe patient was the elder sister of two monochorionic diamniotic twins who was delivered by cesarean section at the gestation age of 37 weeks and 2 days with the birth weight 2.25 kg and body length 45.0 cm. Her father is a hepatitis B virus (HBV) carrier who was clinically healthy but with slightly elevated serum TBA level on biochemistry analysis, and her mother was physically and biochemically healthy (Table ). There was no family history of any genetic disease.\nPhysical examination revealed a body weight of 12.0 kg, height 83.5 cm and head circumference 46.0 cm. No jaundice was observed in the skin and sclera. No stridor, crackles or crepitus was heard in the two lungs, and the heart sound was normal without any murmurs. There was no abdominal distention, and the liver and spleen were non-palpable. Physiological reflexes were normal and no pathological reflexes could be found on nervous system examination. On biochemical analysis, the TBA level reached 173.8 μmol/L (0–10 μmol/L) as other indices were normal (Table ).

Patient 1. A 9-day-old female infant was admitted to the Neonatal Section of our Department of Pediatrics due to jaundice over 6 days. At her age of 3 days, jaundiced skin and sclera was noticed, which was then aggravated progressively. As the second product of a non-consanguineous couple, the infant was spontaneously delivered at the gestation age of 38 weeks and 2 days, with a birth weight of 2.85 kg and a body length 48 cm. The Apgar score was 9 points at 1 min after umbilical ligation, and 10 points at 5 min, while the amniotic fluid was clear. The patient had a 9-year-old brother, who was physically healthy with normal social performance. The parents were healthy, and there was not family history of any genetic disease.\nPhysical examination found a body temperature (T) 36.5°C, heart rate (HR) 140 beats/min , respiratory rate (RR) 45 breaths/min, and a body weight (WT) 2940 g. Jaundice was observed in the skin and sclera. The anterior fontanelle was flat and soft, and no malformation of the head, ears, nose, mouth, and eyes could be observed. No positive signs were found in the two lungs and the heart. Her liver and spleen were not enlarged. The extremities were warm, and the distal perfusion was excellent.\nAfter admission, the liver function test revealed indirect hyperbilirubinemia and markedly elevated serum TBA level. Her jaundice was alleviated soon in a response to phototherapy, but the TBA elevation persisted, even on the following-up in the clinic after she was discharged at the age of 19 days (Table ). When aged 25 days, the infant underwent SLC10A1 analysis to evaluate the possibility of NTCP deficiency. Sanger sequencing of the UGT1A1 gene was performed (), but no pathogenic variant was detected.

Write a detailed clinical case vignette based on the following key phrases: Liver function abnormalities, Genetic disorders, Bile acid metabolism

Patient 3 was a 1-year-and-2-month-old female referred to our hospital because of abnormal liver function discovered for 12.7 months. At the age 1.3 months, she went through a liver function test because of prolonged jaundice for 1 month, which showed raised levels of AST, GGT, ALP, TBIL, DBIL, and IBIL (). When aged 1.8 months, her TBA level was found to be as high as 172.0 µmol/L besides the cholestatic alterations (), and the MS-MS analysis revealed increased levels of tyrosine, citrulline, and methionine while large quantities of urinary 4HPPV and 4HPL were detected on GC-MS analysis. NICCD was consequently suspected, and breast-feeding was stopped while a lactose-free and MCT-enriched formula was suggested. Following that, her cholestatic jaundice got alleviated rapidly and the laboratory alterations recovered to normal levels by the age 5 months, while the hypercholanemia was intractable, even beyond 1 year of age ().\nAs the first child of a non-consanguineous couple, the infant was delivered by cesarean section at the gestation age of 38 weeks and 2 days with the birth weight 2,750 g. Her father was clinically healthy with an elevated serum TBA level of 21.1 µmol/L (0–10 µmol/L), and her mother was physically and biochemically healthy (). There was no family history of any genetic diseases.\nPhysical examination at referral revealed a body weight 10.1 kg, length 80 cm and head circumference 46 cm. No jaundice was observed in the skin and sclera. Examinations of the heart, the lungs, the abdomen, and nervous system were all normal.\nBiochemical test at referral revealed a TBA level 50.9 µmol/L with otherwise normal indices (). On genetic analysis, the patient was a compound heterozygote of the SLC25A13 mutations c.852_855del4 and c.1638_1660dup, which was inherited from the father and mother, respectively (); moreover, the patient and her father were both homozygous for the SLC10A1 variant c.800C > T (p.Ser267Phe), while her mother was a carrier (). Hence, citrin deficiency and NTCP deficiency were definitely diagnosed for the infant. No specific therapy was given, and his TBA level tended downward to 25.6 µmol/L at the age of 3 years and 4 months (), still remaining beyond the upper limit. The patient also had a fondness of protein-rich foods while an aversion to carbohydrate-rich foods from the age 1 year.\nThe molecular findings above were further confirmed by Sanger sequencing () and illustrated as family tree diagrams (). The clinical and molecular features of all the 3 patients were summarized in .

Patient 1. A 9-day-old female infant was admitted to the Neonatal Section of our Department of Pediatrics due to jaundice over 6 days. At her age of 3 days, jaundiced skin and sclera was noticed, which was then aggravated progressively. As the second product of a non-consanguineous couple, the infant was spontaneously delivered at the gestation age of 38 weeks and 2 days, with a birth weight of 2.85 kg and a body length 48 cm. The Apgar score was 9 points at 1 min after umbilical ligation, and 10 points at 5 min, while the amniotic fluid was clear. The patient had a 9-year-old brother, who was physically healthy with normal social performance. The parents were healthy, and there was not family history of any genetic disease.\nPhysical examination found a body temperature (T) 36.5°C, heart rate (HR) 140 beats/min , respiratory rate (RR) 45 breaths/min, and a body weight (WT) 2940 g. Jaundice was observed in the skin and sclera. The anterior fontanelle was flat and soft, and no malformation of the head, ears, nose, mouth, and eyes could be observed. No positive signs were found in the two lungs and the heart. Her liver and spleen were not enlarged. The extremities were warm, and the distal perfusion was excellent.\nAfter admission, the liver function test revealed indirect hyperbilirubinemia and markedly elevated serum TBA level. Her jaundice was alleviated soon in a response to phototherapy, but the TBA elevation persisted, even on the following-up in the clinic after she was discharged at the age of 19 days (Table ). When aged 25 days, the infant underwent SLC10A1 analysis to evaluate the possibility of NTCP deficiency. Sanger sequencing of the UGT1A1 gene was performed (), but no pathogenic variant was detected.

Write a detailed clinical case vignette based on the following key phrases: Liver function abnormalities, Genetic disorders, Bile acid metabolism

A 7-month-old female infant was referred to our hospital due to prolonged jaundice for approximately 4 months and growth retardation for 1.5 months. Her jaundice (yellow skin and sclera) drew the attention of her parents at the age of 3.3 months. A liver function test at the local hospital revealed elevated cholestatic indices, including gamma-glutamyl transpeptidase (GGT), direct bilirubin (Dbil) and total bile acid (TBA) (). Due to the prolonged jaundice and unresolved laboratory abnormalities, the infant was referred to another hospital at the age of 4 months, where magnetic resonance cholangiopancreatography revealed the dilatation of common hepatic and bile ducts. Laparoscopy was thus performed when the infant was aged 4.5 months, and an intraoperative cholangiography displayed biliary tree dilatation and filling defect in the common bile duct, along with an accessory hepatic duct (AHD) joining the cystic duct (). A cholecystectomy was subsequently performed, an intrabiliary thick plug in the color of dark green was removed, and bile duct irrigation and choledochostomy with T-tube drainage was carried out. Pathological analysis of the plug confirmed the diagnosis of inspissated bile syndrome (IBS). Thereafter, the infant’s jaundice subsided and the laboratory indices gradually improved (); the infant was discharged at the age of 5 months. Half a month later, nevertheless, a physical examination revealed that her body weight was 5.34 kg (−3.6 SD), her length was 59 cm (−3.2 SD) and her head circumference was 39 cm (−2.5 SD). Another anthropometric test at the age of 6 months revealed a weight of 6.0 kg (−2.5 SD) and a length of 62.0 cm (−2.2 SD). The growth retardation continued in the following month, and the infant was referred to our hospital at the age of 7 months for further evaluation, following the removal of the drainage T-tube.\nThe infant was born to a non-consanguineous couple after 37 weeks of uneventful gestation with a birth weight of 2.25 kg. On the first day after birth, the infant was admitted to hospital due to vomiting and respiratory distress. Contrast imaging of the upper digestive tract revealed the existence of esophageal atresia (EA) (), which was then resolved by a gastroesophagostomy under general anesthesia. The couple had experienced 2 pregnancies prior to this one, but both were aborted in the first trimester. Both parents appeared healthy, without any clinical symptoms or signs of CTLN2. There was no known family history of any genetic disease.\nPhysical examination at referral revealed a weight of 6.25 kg (−2.6 SD), a length of 63.0 cm (−3.3 SD) and a head circumference of 42 cm (−1.0 SD). There was no dysmorphic appearance, only a slightly chubby face. There was no evidence of jaundice (yellow skin and sclera) and there were no visible petechiae or ecchymoses. No pallor or cyanosis of the lips were observed. There was no tachypnea or dyspnea, and no stridor, wheezes, crackles or crepitus could be heard on auscultation of the both lungs. The heart sounds were normal without audible murmurs or arrhythmia. Upon abdominal inspection, no dilated veins or abdominal distention were observed. The liver was palpated with a soft edge 2 cm below the right costal margin in the mid-clavicular line. Her spleen was not palpable. A neurological examination revealed slightly reduced muscle tone. There was no neck stiffness, knee reflex was normal and there was no positivity for Brudzinski’s or Kernig’s sign.\nFollowing biochemical analysis, no abnormal liver function index was observed, although the serum GGT level was elevated, suggesting the existence of cholestasis, as shown in . Taking into consideration her prolonged jaundice, growth retardation and chubby face, and the 2 first-trimester miscarriages of her mother, SLC25A13 gene analysis was performed on the family to evaluate the possibility of a diagnosis of CD. A lactose-free and MCT-enriched therapeutic formula was subsequently introduced, while a diet rich in protein and lipids was also encouraged. A clinical following-up 4 months later revealed that the weight of the infant was 7.9 kg (−1.6 SD), her length was 70 cm (−1.5 SD) and her head circumference was 44 cm (−0.8 SD), along with a marked improvement (complete recovery) of the cholestatic indices, GGT, TBA and Dbil ().

Patient 1. A 9-day-old female infant was admitted to the Neonatal Section of our Department of Pediatrics due to jaundice over 6 days. At her age of 3 days, jaundiced skin and sclera was noticed, which was then aggravated progressively. As the second product of a non-consanguineous couple, the infant was spontaneously delivered at the gestation age of 38 weeks and 2 days, with a birth weight of 2.85 kg and a body length 48 cm. The Apgar score was 9 points at 1 min after umbilical ligation, and 10 points at 5 min, while the amniotic fluid was clear. The patient had a 9-year-old brother, who was physically healthy with normal social performance. The parents were healthy, and there was not family history of any genetic disease.\nPhysical examination found a body temperature (T) 36.5°C, heart rate (HR) 140 beats/min , respiratory rate (RR) 45 breaths/min, and a body weight (WT) 2940 g. Jaundice was observed in the skin and sclera. The anterior fontanelle was flat and soft, and no malformation of the head, ears, nose, mouth, and eyes could be observed. No positive signs were found in the two lungs and the heart. Her liver and spleen were not enlarged. The extremities were warm, and the distal perfusion was excellent.\nAfter admission, the liver function test revealed indirect hyperbilirubinemia and markedly elevated serum TBA level. Her jaundice was alleviated soon in a response to phototherapy, but the TBA elevation persisted, even on the following-up in the clinic after she was discharged at the age of 19 days (Table ). When aged 25 days, the infant underwent SLC10A1 analysis to evaluate the possibility of NTCP deficiency. Sanger sequencing of the UGT1A1 gene was performed (), but no pathogenic variant was detected.

Write a detailed clinical case vignette based on the following key phrases: Liver function abnormalities, Genetic disorders, Bile acid metabolism

Patient 1. A 9-day-old female infant was admitted to the Neonatal Section of our Department of Pediatrics due to jaundice over 6 days. At her age of 3 days, jaundiced skin and sclera was noticed, which was then aggravated progressively. As the second product of a non-consanguineous couple, the infant was spontaneously delivered at the gestation age of 38 weeks and 2 days, with a birth weight of 2.85 kg and a body length 48 cm. The Apgar score was 9 points at 1 min after umbilical ligation, and 10 points at 5 min, while the amniotic fluid was clear. The patient had a 9-year-old brother, who was physically healthy with normal social performance. The parents were healthy, and there was not family history of any genetic disease.\nPhysical examination found a body temperature (T) 36.5°C, heart rate (HR) 140 beats/min , respiratory rate (RR) 45 breaths/min, and a body weight (WT) 2940 g. Jaundice was observed in the skin and sclera. The anterior fontanelle was flat and soft, and no malformation of the head, ears, nose, mouth, and eyes could be observed. No positive signs were found in the two lungs and the heart. Her liver and spleen were not enlarged. The extremities were warm, and the distal perfusion was excellent.\nAfter admission, the liver function test revealed indirect hyperbilirubinemia and markedly elevated serum TBA level. Her jaundice was alleviated soon in a response to phototherapy, but the TBA elevation persisted, even on the following-up in the clinic after she was discharged at the age of 19 days (Table ). When aged 25 days, the infant underwent SLC10A1 analysis to evaluate the possibility of NTCP deficiency. Sanger sequencing of the UGT1A1 gene was performed (), but no pathogenic variant was detected.

Patient 2. A 5-day-old male infant was admitted to our Neonatal Section because of jaundice for 3 days. Mild jaundice appeared at age 2 days. At the 5th day after birth, the total bilirubin increased to 310.1 μmol/L. Then the infant was referred to our clinic, where a laboratory test revealed elevated TBA as well as indirect hyperbilirubinemia (Table ), and thus the infant was admitted for further management. As the first child of a non-consanguineous couple, the patient was delivered vaginally at the gestational age of 37 weeks with the birth weight 3050 g. The parents were both healthy. Family history of any genetic disease was denied.\nOn physical examination, the body weight was 2910 g, with T 36.2°C, HR 130 beats/min, and RR 43 breaths/min. Jaundiced skin and sclera were observed. The lungs were clear on auscultation, and no abnormal heart sound or murmur was heard. There was no abdominal distention, and the liver and spleen were not palpable. Primitive reflexes were normal and no pathological reflexes could be found on nervous system examination.\nThe patient underwent phototherapy for 3 days. As a result, his jaundice subsided, and he was discharged at age 9 days. No special treatment was given thereafter, and the jaundice did not reappear. However, his serum TBA levels kept high in the following 1 month, and hence SLC10A1 analysis was performed at age 33 days to evaluate the possibility of NTCP deficiency. On Sanger sequencing of the UGT1A1 gene, no pathogenic variant was detected but three benign SNPs in the 3ʹ UTR, i.e. rs10929303, rs1042640 and rs8330 [].

Write a detailed clinical case vignette based on the following key phrases: Liver function abnormalities, Genetic disorders, Bile acid metabolism

Patient 2 was a 1-year-and-1-month-old male visiting our clinic due to hypercholanemia discovered for 11 months. At the age 2 months, he was referred to a local hospital because of prolonged jaundice for about 1 month. On biochemistry analysis, elevated serum levels of AST, GGT, ALP, TBIL, DBIL, and IBIL, together with decreased level of albumin were detected, and notably, the TBA level reached 268.7 µmol/L (). Subsequent urinary GC-MS analysis detected elevated 4-hydroxyphenylpyruvate (4-HPPV) and 4HPL, while raised levels of citrulline, methionine, and threonine were detected on MS-MS analysis of blood sample. When aged 2.1 months, the infant undertook SLC25A13 analysis in our hospital, and proved to be a homozygote of the c.852_855del4 mutation (), and the diagnosis of NICCD was thus made. Then breast-feeding was stopped and a lactose-free and MCT-enriched formula was given. Then his jaundice disappeared rapidly, and serum bilirubin levels returned to normal at his age 5.5 months (). However, the hypercholanemia persisted, even beyond 1 year of age (). No steatorrhea or acholic stool was observed during the course of the disease.\nAs the first child of a non-consanguineous couple, the patient was delivered vaginally at the gestational age of 37 weeks and 4 days with the birth weight 2700 g. The Apgar score was 9 points at 1 min and 10 points at 5 min after umbilical ligation. Parents were both hepatitis B virus (HBV) carriers, who were apparently healthy but with slightly raised serum TBA levels (). Family history of any genetic diseases was denied.\nPhysical examination revealed a body T 36.6°C, weight 10.5 kg, HR 126 bpm, and RR 32 bpm. No jaundiced skin and sclera was observed. On auscultation, no abnormal sounds were heard on the lungs and heart. There was no abdominal distention, and the liver and spleen were non-palpable. Primitive reflexes were normal and pathological reflexes could not be found on nervous system examination.\nLaboratory test at visiting revealed a serum TBA level of 234.5 µmol/L and otherwise normal indices. SLC10A1 genetic analysis demonstrated that the patient was a homozygote, and his parents, carriers, of the variant c.800C > T (p.Ser267Phe) (). The diagnosis of NTCP deficiency was thus made. No specific therapy was given but clinic follow up was suggested. His serum TBA level was 148 µmol/L () when aged 1 year and 6 months, and a fondness for low-carbohydrate and high-protein foods was noticed since the age of 1 year.

Patient 1. A 9-day-old female infant was admitted to the Neonatal Section of our Department of Pediatrics due to jaundice over 6 days. At her age of 3 days, jaundiced skin and sclera was noticed, which was then aggravated progressively. As the second product of a non-consanguineous couple, the infant was spontaneously delivered at the gestation age of 38 weeks and 2 days, with a birth weight of 2.85 kg and a body length 48 cm. The Apgar score was 9 points at 1 min after umbilical ligation, and 10 points at 5 min, while the amniotic fluid was clear. The patient had a 9-year-old brother, who was physically healthy with normal social performance. The parents were healthy, and there was not family history of any genetic disease.\nPhysical examination found a body temperature (T) 36.5°C, heart rate (HR) 140 beats/min , respiratory rate (RR) 45 breaths/min, and a body weight (WT) 2940 g. Jaundice was observed in the skin and sclera. The anterior fontanelle was flat and soft, and no malformation of the head, ears, nose, mouth, and eyes could be observed. No positive signs were found in the two lungs and the heart. Her liver and spleen were not enlarged. The extremities were warm, and the distal perfusion was excellent.\nAfter admission, the liver function test revealed indirect hyperbilirubinemia and markedly elevated serum TBA level. Her jaundice was alleviated soon in a response to phototherapy, but the TBA elevation persisted, even on the following-up in the clinic after she was discharged at the age of 19 days (Table ). When aged 25 days, the infant underwent SLC10A1 analysis to evaluate the possibility of NTCP deficiency. Sanger sequencing of the UGT1A1 gene was performed (), but no pathogenic variant was detected.

Write a detailed clinical case vignette based on the following key phrases: Liver function abnormalities, Genetic disorders, Bile acid metabolism

An 18.5-year-old female was presented to the outpatient clinic due to overweight. Her height was 166.1 cm, her weight was 80.1 kg, and her body mass index (BMI) was 29.0 kg/m2. No clinical signs of hyperandrogenism or hypercortisolism were observed. The skin was normal; however, striae cutis distensae were seen. Neither hirsutism nor acanthosis nigricans was present. No indication of ichthyosis was noted. Pubertal development was complete, with breast stage B5, pubic hair stage PH5, menstrual periods were regular. Blood pressure was within the norm, at 125/80 mm Hg.\nThe patient fulfilled only two criteria for metabolic syndrome in adolescence by having disturbed glucose metabolism and abdominal obesity. Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) was increased to 6.9; oral glucose tolerance was pathological (2 h glucose concentration 165 mg/dl). Serum concentrations of high-density lipoprotein (HDL)-cholesterol (60 mg/dl) and triglycerides (108 mg/dl) were within the reference range, while cholesterol (232 mg/dl) and low-density lipoprotein (LDL)-cholesterol (186 mg/dl) were increased. The patient underwent a relatively successful lifestyle intervention, which enabled a stabilization of her BMI and a normalization of her oral glucose tolerance within 6 months.\nRoutine analysis of adrenal hormones revealed an extremely high serum DHEAS level, at 7,546 ng/ml (reference < 4,000; ). A second blood sample confirmed the DHEAS excess, with even a higher serum level, at 8,835 ng/ml. In contrast, serum DHEA was in the normal range, at 443 ng/dl (reference < 750). Serum ACTH (4.8 pmol/L), cortisol (22.7 μg/dl), androstenedione (10 nmol/L), 17-OH progesterone (70 ng/dl), testosterone (28 ng/dl), luteinizing hormone (LH; 5.7 UI/L), follicle-stimulating hormone (FSH; 1.7 IU/L), as well as thyroid-stimulating hormone (TSH; 1.57 mIU/L), and free thyroxine (fT4; 14 pmol/L) levels were all within the normal range.\nThe serum steroid sulfatome was analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The high DHEAS serum level was confirmed. Interestingly, with the exception of cholesterol sulfate, several other sulfated steroids were found to be above the reference range, namely, pregnenolone sulfate, 17-hydroxypregnenolone sulfate, 16-α-hydroxy-DHEAS, androstenediol-3-sulfate, androsterone sulfate, and epiandrosterone sulfate (). In addition, the urinary steroid metabolome was delineated by gas chromatography-mass spectrometry (GC-MS) in a 24 h urinary sample. It revealed excessive excretion of DHEAS metabolites at 200% of the upper limit of the reference interval. Urinary analysis excluded any known enzyme defect of the adrenal steroid synthesis.\nFor exclusion of an autonomous hormone secretion by an adrenal or an ovarian tumor, administration of 0.5 mg dexamethasone four times daily on four consecutive days was performed which resulted in an efficient suppression of DHEAS and DHEA as well as their urinary metabolites. On day 5, the DHEAS level decreased to 1,199 ng/ml (13.6% of baseline; reference < 47.2%) and the DHEA level to 144 ng/dl (32% of baseline; reference < 38.9%) (). In addition, urinary cortisol metabolites were sufficiently suppressed during the dexamethasone test. Ultrasound and MRI scans of the adrenal glands and the ovaries were normal. No further deterioration in the patient's hormonal investigations was noted during the 4 year course of observation.\nFollowing the hypothesis that the high DHEAS level was likely to be hereditary, we sequenced the STS gene, which is responsible for the hydrolysis of aryl and alkyl steroid sulfates and catalyzes the conversion of DHEAS to DHEA (). Sequence analysis revealed a heterozygous single-base substitution (g.117217G>T) that results in a nonsense mutation at codon 173 (p.G173X). This mutation predicts a truncation of the carboxyl region of the STS enzyme that is implicated in substrate binding. The mutant allele contained two further variants within the fifth exon: a silent mutation (g.117309C>A) at codon 203 C → A (leucine), and a missense mutation at codon 464 G → T, which resulted in substitution of methionine for isoleucine (g.117465G>T). This nonsense mutation is not present in the Exome Variant Server. At 19 bp upstream in the genomic sequence of exon 10, we identified another C → T transition (g.207619C>T). The nonsense mutation p.G173X found in the patient was de novo as demonstrated by allele-specific amplification of the wild-type (wt) and mutant sequences (mut) of both parents' DNA samples. No partial gene deletion of the presumably intact allele outside exon 5 was detected by multiplex ligation-dependent probe amplification.\nBiological activity of STS was measured in the patient's blood leukocytes after addition of 1,2,6,7-3H-DHEAS. In our experimental setting, ~7 nmol DHEA was produced by 1 × 106 leukocytes per 4 h. The mean (SD) STS activity detected in patient's leukocytes was 107% in comparison to those of five healthy age-matched female controls. Therefore, normal hydrolytic activity of STS was revealed in the patient's blood leukocytes.\nNo clear explanation for the high levels of DHEAS connected to the STS gene structure and enzyme activity was found. Therefore, a defect of one or more transporter proteins was suggested (). On the one hand, a reduced steroid sulfate efflux activity in the liver would enhance serum levels; on the other hand, impaired steroid sulfate uptake from the circulation into peripheral target cells or hepatocytes would have the same effect. Prominent candidate efflux transporters were MRP2 and BCRP, both highly expressed at the canalicular membrane of hepatocytes and involved in the hepatobiliary elimination of many drugs and some endogenous substrates such as sulfated steroids (). However, as MRP2 deficiency would typically increase the levels of conjugated bilirubin in the plasma (Dubin–Johnson syndrome) () what was not seen in the patient, BCRP was the only candidate carrier for the efflux site. On the uptake site, several OATP and OAT carriers were on the list. However, as most of them show highly overlapping substrate specificities and redundant expression patterns (e.g., OATP1B1, OATP1B3, and OATP2B1 are expressed in the liver) (), it was supposed that a transport defect of one of these carriers could have been compensated by another member of the same carrier family. Therefore, we decided to select two carriers from the SLC10 carrier family, which are more unique in the sense of substrate specificity and tissue expression and which both show sodium-dependent transport of sulfated steroids (, ). In both carriers, genetic variants or mutations were described before with significantly reduced transport activity, associated with increased plasma levels of their substrates (–). However, as the determination of DHEAS serum levels is not included in standard diagnostics, elevated DHEAS levels may have been overseen in patients with such carrier defects. Using exon-spanning PCR, all exons of the abovementioned membrane transporters were sequenced. There were no relevant variants detected for the SLC10A1 and SLC10A6 genes. Sequence analysis revealed a heterozygous Q141K variant for BCRP. Interestingly, this variant has in its homozygous state previously been associated with reduced efflux transport activity ().

Patient 1. A 9-day-old female infant was admitted to the Neonatal Section of our Department of Pediatrics due to jaundice over 6 days. At her age of 3 days, jaundiced skin and sclera was noticed, which was then aggravated progressively. As the second product of a non-consanguineous couple, the infant was spontaneously delivered at the gestation age of 38 weeks and 2 days, with a birth weight of 2.85 kg and a body length 48 cm. The Apgar score was 9 points at 1 min after umbilical ligation, and 10 points at 5 min, while the amniotic fluid was clear. The patient had a 9-year-old brother, who was physically healthy with normal social performance. The parents were healthy, and there was not family history of any genetic disease.\nPhysical examination found a body temperature (T) 36.5°C, heart rate (HR) 140 beats/min , respiratory rate (RR) 45 breaths/min, and a body weight (WT) 2940 g. Jaundice was observed in the skin and sclera. The anterior fontanelle was flat and soft, and no malformation of the head, ears, nose, mouth, and eyes could be observed. No positive signs were found in the two lungs and the heart. Her liver and spleen were not enlarged. The extremities were warm, and the distal perfusion was excellent.\nAfter admission, the liver function test revealed indirect hyperbilirubinemia and markedly elevated serum TBA level. Her jaundice was alleviated soon in a response to phototherapy, but the TBA elevation persisted, even on the following-up in the clinic after she was discharged at the age of 19 days (Table ). When aged 25 days, the infant underwent SLC10A1 analysis to evaluate the possibility of NTCP deficiency. Sanger sequencing of the UGT1A1 gene was performed (), but no pathogenic variant was detected.

Write a detailed clinical case vignette based on the following key phrases: Liver function abnormalities, Genetic disorders, Bile acid metabolism

Patient 1 was a 5–year-and-11-month-old female referred to the First Affiliated Hospital, Jinan University due to abnormal liver function discovered for 5 years and 7 months. When aged 4 months, she was admitted to a hospital in Guangzhou due to jaundice for 3 months, where physical examination revealed an enlarged liver 4.0 cm below the right costal margin, and a liver function test revealed elevated serum levels of total bilirubin (TBIL), direct bilirubin (DBIL), indirect bilirubin (IBIL), alanine transaminase (ALT), aspartate transaminase (AST), γ-glutamyl transpeptidase (GGT), and alkaline phosphatase (ALP), indicating cholestatic jaundice (). Blood amino acid spectrum analysis by tandem mass spectrometry (MS-MS) revealed raised citrulline, methionine, arginine, and threonine, while large quantities of galactose, galactitol, galactonate, and 4-hydroxyphenyllactate (4HPL) were detected on urinary gas chromatography-mass spectrometry (GC-MS) analysis. Considering the above clinical and laboratory findings, NICCD was suspected, and breast-feeding was stopped while a lactose-free and medium-chain triglycerides (MCT)-enriched formula was introduced. When aged 4.9 months, SLC25A13 genetic analysis in our hospital unveiled a homozygote of the c.852_855del4 mutation () and the diagnosis of NICCD was hence made. Thereafter, besides feeding with the therapeutic formula, supplemental foods rich in protein were encouraged. As a result, her liver function indices got improved gradually and returned to normal by age 10.2 months. However, the hypercholanemia was refractory, with total bile acid (TBA) levels fluctuating from 27.6 µmol/L to 340.2 µmol/L (reference range: 0–10 µmol/L) (). After the age 2 years, the patient showed a fondness for foods rich in protein and fat while an aversion to carbohydrate-rich diets.\nAs the first product of a non-consanguineous couple, the child was delivered spontaneously at the gestational age of 38 weeks and 3 days after an uneventful pregnancy, with a birth weight of 3.0 kg and body length 50 cm. The parents were healthy, and there was no family history of any genetic or infectious diseases.\nPhysical examination revealed a body temperature (T) 36.5°C, heart rate (HR) 115 beats/min (bpm), respiratory rate (RR) 20 bpm, weight (WT) 18 kg, height 107.0 cm. No jaundice was observed in the skin and sclera. The lungs were clear. No murmurs or abnormal heart sounds were heard. There was no abdominal distention, and the liver and spleen were not enlarged. Physiological reflexes were normal and no pathological reflexes could be found on nervous system examination. The extremities were warm, and the distal perfusion was excellent.\nLaboratory investigation showed otherwise normal biochemical indices but a TBA level of 48.7 µmol/L. In view of the intractable hypercholanemia, NTCP deficiency was highly suspected, and SLC10A1 genetic analysis was performed. As a result, the patient was a homozygote, while the parents, carriers, of the reportedly pathogenic variant c.800C > T(p.Ser267Phe)(). NTCP deficiency was thus definitely diagnosed. No specific therapy was given but close clinic follow-up was underway.

Patient 1. A 9-day-old female infant was admitted to the Neonatal Section of our Department of Pediatrics due to jaundice over 6 days. At her age of 3 days, jaundiced skin and sclera was noticed, which was then aggravated progressively. As the second product of a non-consanguineous couple, the infant was spontaneously delivered at the gestation age of 38 weeks and 2 days, with a birth weight of 2.85 kg and a body length 48 cm. The Apgar score was 9 points at 1 min after umbilical ligation, and 10 points at 5 min, while the amniotic fluid was clear. The patient had a 9-year-old brother, who was physically healthy with normal social performance. The parents were healthy, and there was not family history of any genetic disease.\nPhysical examination found a body temperature (T) 36.5°C, heart rate (HR) 140 beats/min , respiratory rate (RR) 45 breaths/min, and a body weight (WT) 2940 g. Jaundice was observed in the skin and sclera. The anterior fontanelle was flat and soft, and no malformation of the head, ears, nose, mouth, and eyes could be observed. No positive signs were found in the two lungs and the heart. Her liver and spleen were not enlarged. The extremities were warm, and the distal perfusion was excellent.\nAfter admission, the liver function test revealed indirect hyperbilirubinemia and markedly elevated serum TBA level. Her jaundice was alleviated soon in a response to phototherapy, but the TBA elevation persisted, even on the following-up in the clinic after she was discharged at the age of 19 days (Table ). When aged 25 days, the infant underwent SLC10A1 analysis to evaluate the possibility of NTCP deficiency. Sanger sequencing of the UGT1A1 gene was performed (), but no pathogenic variant was detected.

Write a detailed clinical case vignette based on the following key phrases: Liver function abnormalities, Genetic disorders, Bile acid metabolism

Patient 3 was a 1-year-and-2-month-old female referred to our hospital because of abnormal liver function discovered for 12.7 months. At the age 1.3 months, she went through a liver function test because of prolonged jaundice for 1 month, which showed raised levels of AST, GGT, ALP, TBIL, DBIL, and IBIL (). When aged 1.8 months, her TBA level was found to be as high as 172.0 µmol/L besides the cholestatic alterations (), and the MS-MS analysis revealed increased levels of tyrosine, citrulline, and methionine while large quantities of urinary 4HPPV and 4HPL were detected on GC-MS analysis. NICCD was consequently suspected, and breast-feeding was stopped while a lactose-free and MCT-enriched formula was suggested. Following that, her cholestatic jaundice got alleviated rapidly and the laboratory alterations recovered to normal levels by the age 5 months, while the hypercholanemia was intractable, even beyond 1 year of age ().\nAs the first child of a non-consanguineous couple, the infant was delivered by cesarean section at the gestation age of 38 weeks and 2 days with the birth weight 2,750 g. Her father was clinically healthy with an elevated serum TBA level of 21.1 µmol/L (0–10 µmol/L), and her mother was physically and biochemically healthy (). There was no family history of any genetic diseases.\nPhysical examination at referral revealed a body weight 10.1 kg, length 80 cm and head circumference 46 cm. No jaundice was observed in the skin and sclera. Examinations of the heart, the lungs, the abdomen, and nervous system were all normal.\nBiochemical test at referral revealed a TBA level 50.9 µmol/L with otherwise normal indices (). On genetic analysis, the patient was a compound heterozygote of the SLC25A13 mutations c.852_855del4 and c.1638_1660dup, which was inherited from the father and mother, respectively (); moreover, the patient and her father were both homozygous for the SLC10A1 variant c.800C > T (p.Ser267Phe), while her mother was a carrier (). Hence, citrin deficiency and NTCP deficiency were definitely diagnosed for the infant. No specific therapy was given, and his TBA level tended downward to 25.6 µmol/L at the age of 3 years and 4 months (), still remaining beyond the upper limit. The patient also had a fondness of protein-rich foods while an aversion to carbohydrate-rich foods from the age 1 year.\nThe molecular findings above were further confirmed by Sanger sequencing () and illustrated as family tree diagrams (). The clinical and molecular features of all the 3 patients were summarized in .

Patient 1. A 2-years-old female infant was referred to the First Affiliated Hospital, Jinan University, due to elevated serum total bile acids (TBA) discovered for 21 months. At the age 3 months, she was admitted to Women and Children's Hospital of Quanzhou because of jaundice for 2 months. Laboratory test revealed that the serum levels of TBA, direct bilirubin (DBIL), aspartate transaminase (AST) and alanine transaminase (ALT) were all elevated (Table ), and she was thus diagnosed to have cholestatic liver disease. After being treated with intravenous reduced glutathione and ademetionine-1,4-butanedisulfonate for 9 days, which were commonly used in cholestatic patients with elevated alanine transaminase levels, her jaundice was alleviated, but the liver function indices remained abnormal (Table ). Then oral ursodesoxycholic acid was given and she was discharged at the age 3.3 months. During the subsequent follow-up over 20 months, she showed normal anthropometric and neurobehavioral development without abnormal appearance, and her cholestasis resolved completely since the age 7 months. However, persistently raised TBA levels were observed on repeated biochemical analyses (Table ). So she was referred to our hospital for further investigation and management when aged 2 years.\nThe patient was the elder sister of two monochorionic diamniotic twins who was delivered by cesarean section at the gestation age of 37 weeks and 2 days with the birth weight 2.25 kg and body length 45.0 cm. Her father is a hepatitis B virus (HBV) carrier who was clinically healthy but with slightly elevated serum TBA level on biochemistry analysis, and her mother was physically and biochemically healthy (Table ). There was no family history of any genetic disease.\nPhysical examination revealed a body weight of 12.0 kg, height 83.5 cm and head circumference 46.0 cm. No jaundice was observed in the skin and sclera. No stridor, crackles or crepitus was heard in the two lungs, and the heart sound was normal without any murmurs. There was no abdominal distention, and the liver and spleen were non-palpable. Physiological reflexes were normal and no pathological reflexes could be found on nervous system examination. On biochemical analysis, the TBA level reached 173.8 μmol/L (0–10 μmol/L) as other indices were normal (Table ).

Write a detailed clinical case vignette based on the following key phrases: Liver function abnormalities, Genetic disorders, Bile acid metabolism

Patient 1. A 2-years-old female infant was referred to the First Affiliated Hospital, Jinan University, due to elevated serum total bile acids (TBA) discovered for 21 months. At the age 3 months, she was admitted to Women and Children's Hospital of Quanzhou because of jaundice for 2 months. Laboratory test revealed that the serum levels of TBA, direct bilirubin (DBIL), aspartate transaminase (AST) and alanine transaminase (ALT) were all elevated (Table ), and she was thus diagnosed to have cholestatic liver disease. After being treated with intravenous reduced glutathione and ademetionine-1,4-butanedisulfonate for 9 days, which were commonly used in cholestatic patients with elevated alanine transaminase levels, her jaundice was alleviated, but the liver function indices remained abnormal (Table ). Then oral ursodesoxycholic acid was given and she was discharged at the age 3.3 months. During the subsequent follow-up over 20 months, she showed normal anthropometric and neurobehavioral development without abnormal appearance, and her cholestasis resolved completely since the age 7 months. However, persistently raised TBA levels were observed on repeated biochemical analyses (Table ). So she was referred to our hospital for further investigation and management when aged 2 years.\nThe patient was the elder sister of two monochorionic diamniotic twins who was delivered by cesarean section at the gestation age of 37 weeks and 2 days with the birth weight 2.25 kg and body length 45.0 cm. Her father is a hepatitis B virus (HBV) carrier who was clinically healthy but with slightly elevated serum TBA level on biochemistry analysis, and her mother was physically and biochemically healthy (Table ). There was no family history of any genetic disease.\nPhysical examination revealed a body weight of 12.0 kg, height 83.5 cm and head circumference 46.0 cm. No jaundice was observed in the skin and sclera. No stridor, crackles or crepitus was heard in the two lungs, and the heart sound was normal without any murmurs. There was no abdominal distention, and the liver and spleen were non-palpable. Physiological reflexes were normal and no pathological reflexes could be found on nervous system examination. On biochemical analysis, the TBA level reached 173.8 μmol/L (0–10 μmol/L) as other indices were normal (Table ).

A 7-month-old female infant was referred to our hospital due to prolonged jaundice for approximately 4 months and growth retardation for 1.5 months. Her jaundice (yellow skin and sclera) drew the attention of her parents at the age of 3.3 months. A liver function test at the local hospital revealed elevated cholestatic indices, including gamma-glutamyl transpeptidase (GGT), direct bilirubin (Dbil) and total bile acid (TBA) (). Due to the prolonged jaundice and unresolved laboratory abnormalities, the infant was referred to another hospital at the age of 4 months, where magnetic resonance cholangiopancreatography revealed the dilatation of common hepatic and bile ducts. Laparoscopy was thus performed when the infant was aged 4.5 months, and an intraoperative cholangiography displayed biliary tree dilatation and filling defect in the common bile duct, along with an accessory hepatic duct (AHD) joining the cystic duct (). A cholecystectomy was subsequently performed, an intrabiliary thick plug in the color of dark green was removed, and bile duct irrigation and choledochostomy with T-tube drainage was carried out. Pathological analysis of the plug confirmed the diagnosis of inspissated bile syndrome (IBS). Thereafter, the infant’s jaundice subsided and the laboratory indices gradually improved (); the infant was discharged at the age of 5 months. Half a month later, nevertheless, a physical examination revealed that her body weight was 5.34 kg (−3.6 SD), her length was 59 cm (−3.2 SD) and her head circumference was 39 cm (−2.5 SD). Another anthropometric test at the age of 6 months revealed a weight of 6.0 kg (−2.5 SD) and a length of 62.0 cm (−2.2 SD). The growth retardation continued in the following month, and the infant was referred to our hospital at the age of 7 months for further evaluation, following the removal of the drainage T-tube.\nThe infant was born to a non-consanguineous couple after 37 weeks of uneventful gestation with a birth weight of 2.25 kg. On the first day after birth, the infant was admitted to hospital due to vomiting and respiratory distress. Contrast imaging of the upper digestive tract revealed the existence of esophageal atresia (EA) (), which was then resolved by a gastroesophagostomy under general anesthesia. The couple had experienced 2 pregnancies prior to this one, but both were aborted in the first trimester. Both parents appeared healthy, without any clinical symptoms or signs of CTLN2. There was no known family history of any genetic disease.\nPhysical examination at referral revealed a weight of 6.25 kg (−2.6 SD), a length of 63.0 cm (−3.3 SD) and a head circumference of 42 cm (−1.0 SD). There was no dysmorphic appearance, only a slightly chubby face. There was no evidence of jaundice (yellow skin and sclera) and there were no visible petechiae or ecchymoses. No pallor or cyanosis of the lips were observed. There was no tachypnea or dyspnea, and no stridor, wheezes, crackles or crepitus could be heard on auscultation of the both lungs. The heart sounds were normal without audible murmurs or arrhythmia. Upon abdominal inspection, no dilated veins or abdominal distention were observed. The liver was palpated with a soft edge 2 cm below the right costal margin in the mid-clavicular line. Her spleen was not palpable. A neurological examination revealed slightly reduced muscle tone. There was no neck stiffness, knee reflex was normal and there was no positivity for Brudzinski’s or Kernig’s sign.\nFollowing biochemical analysis, no abnormal liver function index was observed, although the serum GGT level was elevated, suggesting the existence of cholestasis, as shown in . Taking into consideration her prolonged jaundice, growth retardation and chubby face, and the 2 first-trimester miscarriages of her mother, SLC25A13 gene analysis was performed on the family to evaluate the possibility of a diagnosis of CD. A lactose-free and MCT-enriched therapeutic formula was subsequently introduced, while a diet rich in protein and lipids was also encouraged. A clinical following-up 4 months later revealed that the weight of the infant was 7.9 kg (−1.6 SD), her length was 70 cm (−1.5 SD) and her head circumference was 44 cm (−0.8 SD), along with a marked improvement (complete recovery) of the cholestatic indices, GGT, TBA and Dbil ().

Write a detailed clinical case vignette based on the following key phrases: Liver function abnormalities, Genetic disorders, Bile acid metabolism

Patient 1. A 2-years-old female infant was referred to the First Affiliated Hospital, Jinan University, due to elevated serum total bile acids (TBA) discovered for 21 months. At the age 3 months, she was admitted to Women and Children's Hospital of Quanzhou because of jaundice for 2 months. Laboratory test revealed that the serum levels of TBA, direct bilirubin (DBIL), aspartate transaminase (AST) and alanine transaminase (ALT) were all elevated (Table ), and she was thus diagnosed to have cholestatic liver disease. After being treated with intravenous reduced glutathione and ademetionine-1,4-butanedisulfonate for 9 days, which were commonly used in cholestatic patients with elevated alanine transaminase levels, her jaundice was alleviated, but the liver function indices remained abnormal (Table ). Then oral ursodesoxycholic acid was given and she was discharged at the age 3.3 months. During the subsequent follow-up over 20 months, she showed normal anthropometric and neurobehavioral development without abnormal appearance, and her cholestasis resolved completely since the age 7 months. However, persistently raised TBA levels were observed on repeated biochemical analyses (Table ). So she was referred to our hospital for further investigation and management when aged 2 years.\nThe patient was the elder sister of two monochorionic diamniotic twins who was delivered by cesarean section at the gestation age of 37 weeks and 2 days with the birth weight 2.25 kg and body length 45.0 cm. Her father is a hepatitis B virus (HBV) carrier who was clinically healthy but with slightly elevated serum TBA level on biochemistry analysis, and her mother was physically and biochemically healthy (Table ). There was no family history of any genetic disease.\nPhysical examination revealed a body weight of 12.0 kg, height 83.5 cm and head circumference 46.0 cm. No jaundice was observed in the skin and sclera. No stridor, crackles or crepitus was heard in the two lungs, and the heart sound was normal without any murmurs. There was no abdominal distention, and the liver and spleen were non-palpable. Physiological reflexes were normal and no pathological reflexes could be found on nervous system examination. On biochemical analysis, the TBA level reached 173.8 μmol/L (0–10 μmol/L) as other indices were normal (Table ).

Patient 2. A 5-day-old male infant was admitted to our Neonatal Section because of jaundice for 3 days. Mild jaundice appeared at age 2 days. At the 5th day after birth, the total bilirubin increased to 310.1 μmol/L. Then the infant was referred to our clinic, where a laboratory test revealed elevated TBA as well as indirect hyperbilirubinemia (Table ), and thus the infant was admitted for further management. As the first child of a non-consanguineous couple, the patient was delivered vaginally at the gestational age of 37 weeks with the birth weight 3050 g. The parents were both healthy. Family history of any genetic disease was denied.\nOn physical examination, the body weight was 2910 g, with T 36.2°C, HR 130 beats/min, and RR 43 breaths/min. Jaundiced skin and sclera were observed. The lungs were clear on auscultation, and no abnormal heart sound or murmur was heard. There was no abdominal distention, and the liver and spleen were not palpable. Primitive reflexes were normal and no pathological reflexes could be found on nervous system examination.\nThe patient underwent phototherapy for 3 days. As a result, his jaundice subsided, and he was discharged at age 9 days. No special treatment was given thereafter, and the jaundice did not reappear. However, his serum TBA levels kept high in the following 1 month, and hence SLC10A1 analysis was performed at age 33 days to evaluate the possibility of NTCP deficiency. On Sanger sequencing of the UGT1A1 gene, no pathogenic variant was detected but three benign SNPs in the 3ʹ UTR, i.e. rs10929303, rs1042640 and rs8330 [].

Write a detailed clinical case vignette based on the following key phrases: Liver function abnormalities, Genetic disorders, Bile acid metabolism

Patient 2 was a 1-year-and-1-month-old male visiting our clinic due to hypercholanemia discovered for 11 months. At the age 2 months, he was referred to a local hospital because of prolonged jaundice for about 1 month. On biochemistry analysis, elevated serum levels of AST, GGT, ALP, TBIL, DBIL, and IBIL, together with decreased level of albumin were detected, and notably, the TBA level reached 268.7 µmol/L (). Subsequent urinary GC-MS analysis detected elevated 4-hydroxyphenylpyruvate (4-HPPV) and 4HPL, while raised levels of citrulline, methionine, and threonine were detected on MS-MS analysis of blood sample. When aged 2.1 months, the infant undertook SLC25A13 analysis in our hospital, and proved to be a homozygote of the c.852_855del4 mutation (), and the diagnosis of NICCD was thus made. Then breast-feeding was stopped and a lactose-free and MCT-enriched formula was given. Then his jaundice disappeared rapidly, and serum bilirubin levels returned to normal at his age 5.5 months (). However, the hypercholanemia persisted, even beyond 1 year of age (). No steatorrhea or acholic stool was observed during the course of the disease.\nAs the first child of a non-consanguineous couple, the patient was delivered vaginally at the gestational age of 37 weeks and 4 days with the birth weight 2700 g. The Apgar score was 9 points at 1 min and 10 points at 5 min after umbilical ligation. Parents were both hepatitis B virus (HBV) carriers, who were apparently healthy but with slightly raised serum TBA levels (). Family history of any genetic diseases was denied.\nPhysical examination revealed a body T 36.6°C, weight 10.5 kg, HR 126 bpm, and RR 32 bpm. No jaundiced skin and sclera was observed. On auscultation, no abnormal sounds were heard on the lungs and heart. There was no abdominal distention, and the liver and spleen were non-palpable. Primitive reflexes were normal and pathological reflexes could not be found on nervous system examination.\nLaboratory test at visiting revealed a serum TBA level of 234.5 µmol/L and otherwise normal indices. SLC10A1 genetic analysis demonstrated that the patient was a homozygote, and his parents, carriers, of the variant c.800C > T (p.Ser267Phe) (). The diagnosis of NTCP deficiency was thus made. No specific therapy was given but clinic follow up was suggested. His serum TBA level was 148 µmol/L () when aged 1 year and 6 months, and a fondness for low-carbohydrate and high-protein foods was noticed since the age of 1 year.

Patient 1. A 2-years-old female infant was referred to the First Affiliated Hospital, Jinan University, due to elevated serum total bile acids (TBA) discovered for 21 months. At the age 3 months, she was admitted to Women and Children's Hospital of Quanzhou because of jaundice for 2 months. Laboratory test revealed that the serum levels of TBA, direct bilirubin (DBIL), aspartate transaminase (AST) and alanine transaminase (ALT) were all elevated (Table ), and she was thus diagnosed to have cholestatic liver disease. After being treated with intravenous reduced glutathione and ademetionine-1,4-butanedisulfonate for 9 days, which were commonly used in cholestatic patients with elevated alanine transaminase levels, her jaundice was alleviated, but the liver function indices remained abnormal (Table ). Then oral ursodesoxycholic acid was given and she was discharged at the age 3.3 months. During the subsequent follow-up over 20 months, she showed normal anthropometric and neurobehavioral development without abnormal appearance, and her cholestasis resolved completely since the age 7 months. However, persistently raised TBA levels were observed on repeated biochemical analyses (Table ). So she was referred to our hospital for further investigation and management when aged 2 years.\nThe patient was the elder sister of two monochorionic diamniotic twins who was delivered by cesarean section at the gestation age of 37 weeks and 2 days with the birth weight 2.25 kg and body length 45.0 cm. Her father is a hepatitis B virus (HBV) carrier who was clinically healthy but with slightly elevated serum TBA level on biochemistry analysis, and her mother was physically and biochemically healthy (Table ). There was no family history of any genetic disease.\nPhysical examination revealed a body weight of 12.0 kg, height 83.5 cm and head circumference 46.0 cm. No jaundice was observed in the skin and sclera. No stridor, crackles or crepitus was heard in the two lungs, and the heart sound was normal without any murmurs. There was no abdominal distention, and the liver and spleen were non-palpable. Physiological reflexes were normal and no pathological reflexes could be found on nervous system examination. On biochemical analysis, the TBA level reached 173.8 μmol/L (0–10 μmol/L) as other indices were normal (Table ).

Write a detailed clinical case vignette based on the following key phrases: Liver function abnormalities, Genetic disorders, Bile acid metabolism

An 18.5-year-old female was presented to the outpatient clinic due to overweight. Her height was 166.1 cm, her weight was 80.1 kg, and her body mass index (BMI) was 29.0 kg/m2. No clinical signs of hyperandrogenism or hypercortisolism were observed. The skin was normal; however, striae cutis distensae were seen. Neither hirsutism nor acanthosis nigricans was present. No indication of ichthyosis was noted. Pubertal development was complete, with breast stage B5, pubic hair stage PH5, menstrual periods were regular. Blood pressure was within the norm, at 125/80 mm Hg.\nThe patient fulfilled only two criteria for metabolic syndrome in adolescence by having disturbed glucose metabolism and abdominal obesity. Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) was increased to 6.9; oral glucose tolerance was pathological (2 h glucose concentration 165 mg/dl). Serum concentrations of high-density lipoprotein (HDL)-cholesterol (60 mg/dl) and triglycerides (108 mg/dl) were within the reference range, while cholesterol (232 mg/dl) and low-density lipoprotein (LDL)-cholesterol (186 mg/dl) were increased. The patient underwent a relatively successful lifestyle intervention, which enabled a stabilization of her BMI and a normalization of her oral glucose tolerance within 6 months.\nRoutine analysis of adrenal hormones revealed an extremely high serum DHEAS level, at 7,546 ng/ml (reference < 4,000; ). A second blood sample confirmed the DHEAS excess, with even a higher serum level, at 8,835 ng/ml. In contrast, serum DHEA was in the normal range, at 443 ng/dl (reference < 750). Serum ACTH (4.8 pmol/L), cortisol (22.7 μg/dl), androstenedione (10 nmol/L), 17-OH progesterone (70 ng/dl), testosterone (28 ng/dl), luteinizing hormone (LH; 5.7 UI/L), follicle-stimulating hormone (FSH; 1.7 IU/L), as well as thyroid-stimulating hormone (TSH; 1.57 mIU/L), and free thyroxine (fT4; 14 pmol/L) levels were all within the normal range.\nThe serum steroid sulfatome was analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The high DHEAS serum level was confirmed. Interestingly, with the exception of cholesterol sulfate, several other sulfated steroids were found to be above the reference range, namely, pregnenolone sulfate, 17-hydroxypregnenolone sulfate, 16-α-hydroxy-DHEAS, androstenediol-3-sulfate, androsterone sulfate, and epiandrosterone sulfate (). In addition, the urinary steroid metabolome was delineated by gas chromatography-mass spectrometry (GC-MS) in a 24 h urinary sample. It revealed excessive excretion of DHEAS metabolites at 200% of the upper limit of the reference interval. Urinary analysis excluded any known enzyme defect of the adrenal steroid synthesis.\nFor exclusion of an autonomous hormone secretion by an adrenal or an ovarian tumor, administration of 0.5 mg dexamethasone four times daily on four consecutive days was performed which resulted in an efficient suppression of DHEAS and DHEA as well as their urinary metabolites. On day 5, the DHEAS level decreased to 1,199 ng/ml (13.6% of baseline; reference < 47.2%) and the DHEA level to 144 ng/dl (32% of baseline; reference < 38.9%) (). In addition, urinary cortisol metabolites were sufficiently suppressed during the dexamethasone test. Ultrasound and MRI scans of the adrenal glands and the ovaries were normal. No further deterioration in the patient's hormonal investigations was noted during the 4 year course of observation.\nFollowing the hypothesis that the high DHEAS level was likely to be hereditary, we sequenced the STS gene, which is responsible for the hydrolysis of aryl and alkyl steroid sulfates and catalyzes the conversion of DHEAS to DHEA (). Sequence analysis revealed a heterozygous single-base substitution (g.117217G>T) that results in a nonsense mutation at codon 173 (p.G173X). This mutation predicts a truncation of the carboxyl region of the STS enzyme that is implicated in substrate binding. The mutant allele contained two further variants within the fifth exon: a silent mutation (g.117309C>A) at codon 203 C → A (leucine), and a missense mutation at codon 464 G → T, which resulted in substitution of methionine for isoleucine (g.117465G>T). This nonsense mutation is not present in the Exome Variant Server. At 19 bp upstream in the genomic sequence of exon 10, we identified another C → T transition (g.207619C>T). The nonsense mutation p.G173X found in the patient was de novo as demonstrated by allele-specific amplification of the wild-type (wt) and mutant sequences (mut) of both parents' DNA samples. No partial gene deletion of the presumably intact allele outside exon 5 was detected by multiplex ligation-dependent probe amplification.\nBiological activity of STS was measured in the patient's blood leukocytes after addition of 1,2,6,7-3H-DHEAS. In our experimental setting, ~7 nmol DHEA was produced by 1 × 106 leukocytes per 4 h. The mean (SD) STS activity detected in patient's leukocytes was 107% in comparison to those of five healthy age-matched female controls. Therefore, normal hydrolytic activity of STS was revealed in the patient's blood leukocytes.\nNo clear explanation for the high levels of DHEAS connected to the STS gene structure and enzyme activity was found. Therefore, a defect of one or more transporter proteins was suggested (). On the one hand, a reduced steroid sulfate efflux activity in the liver would enhance serum levels; on the other hand, impaired steroid sulfate uptake from the circulation into peripheral target cells or hepatocytes would have the same effect. Prominent candidate efflux transporters were MRP2 and BCRP, both highly expressed at the canalicular membrane of hepatocytes and involved in the hepatobiliary elimination of many drugs and some endogenous substrates such as sulfated steroids (). However, as MRP2 deficiency would typically increase the levels of conjugated bilirubin in the plasma (Dubin–Johnson syndrome) () what was not seen in the patient, BCRP was the only candidate carrier for the efflux site. On the uptake site, several OATP and OAT carriers were on the list. However, as most of them show highly overlapping substrate specificities and redundant expression patterns (e.g., OATP1B1, OATP1B3, and OATP2B1 are expressed in the liver) (), it was supposed that a transport defect of one of these carriers could have been compensated by another member of the same carrier family. Therefore, we decided to select two carriers from the SLC10 carrier family, which are more unique in the sense of substrate specificity and tissue expression and which both show sodium-dependent transport of sulfated steroids (, ). In both carriers, genetic variants or mutations were described before with significantly reduced transport activity, associated with increased plasma levels of their substrates (–). However, as the determination of DHEAS serum levels is not included in standard diagnostics, elevated DHEAS levels may have been overseen in patients with such carrier defects. Using exon-spanning PCR, all exons of the abovementioned membrane transporters were sequenced. There were no relevant variants detected for the SLC10A1 and SLC10A6 genes. Sequence analysis revealed a heterozygous Q141K variant for BCRP. Interestingly, this variant has in its homozygous state previously been associated with reduced efflux transport activity ().

Patient 1. A 2-years-old female infant was referred to the First Affiliated Hospital, Jinan University, due to elevated serum total bile acids (TBA) discovered for 21 months. At the age 3 months, she was admitted to Women and Children's Hospital of Quanzhou because of jaundice for 2 months. Laboratory test revealed that the serum levels of TBA, direct bilirubin (DBIL), aspartate transaminase (AST) and alanine transaminase (ALT) were all elevated (Table ), and she was thus diagnosed to have cholestatic liver disease. After being treated with intravenous reduced glutathione and ademetionine-1,4-butanedisulfonate for 9 days, which were commonly used in cholestatic patients with elevated alanine transaminase levels, her jaundice was alleviated, but the liver function indices remained abnormal (Table ). Then oral ursodesoxycholic acid was given and she was discharged at the age 3.3 months. During the subsequent follow-up over 20 months, she showed normal anthropometric and neurobehavioral development without abnormal appearance, and her cholestasis resolved completely since the age 7 months. However, persistently raised TBA levels were observed on repeated biochemical analyses (Table ). So she was referred to our hospital for further investigation and management when aged 2 years.\nThe patient was the elder sister of two monochorionic diamniotic twins who was delivered by cesarean section at the gestation age of 37 weeks and 2 days with the birth weight 2.25 kg and body length 45.0 cm. Her father is a hepatitis B virus (HBV) carrier who was clinically healthy but with slightly elevated serum TBA level on biochemistry analysis, and her mother was physically and biochemically healthy (Table ). There was no family history of any genetic disease.\nPhysical examination revealed a body weight of 12.0 kg, height 83.5 cm and head circumference 46.0 cm. No jaundice was observed in the skin and sclera. No stridor, crackles or crepitus was heard in the two lungs, and the heart sound was normal without any murmurs. There was no abdominal distention, and the liver and spleen were non-palpable. Physiological reflexes were normal and no pathological reflexes could be found on nervous system examination. On biochemical analysis, the TBA level reached 173.8 μmol/L (0–10 μmol/L) as other indices were normal (Table ).

Write a detailed clinical case vignette based on the following key phrases: Liver function abnormalities, Genetic disorders, Bile acid metabolism

Patient 1 was a 5–year-and-11-month-old female referred to the First Affiliated Hospital, Jinan University due to abnormal liver function discovered for 5 years and 7 months. When aged 4 months, she was admitted to a hospital in Guangzhou due to jaundice for 3 months, where physical examination revealed an enlarged liver 4.0 cm below the right costal margin, and a liver function test revealed elevated serum levels of total bilirubin (TBIL), direct bilirubin (DBIL), indirect bilirubin (IBIL), alanine transaminase (ALT), aspartate transaminase (AST), γ-glutamyl transpeptidase (GGT), and alkaline phosphatase (ALP), indicating cholestatic jaundice (). Blood amino acid spectrum analysis by tandem mass spectrometry (MS-MS) revealed raised citrulline, methionine, arginine, and threonine, while large quantities of galactose, galactitol, galactonate, and 4-hydroxyphenyllactate (4HPL) were detected on urinary gas chromatography-mass spectrometry (GC-MS) analysis. Considering the above clinical and laboratory findings, NICCD was suspected, and breast-feeding was stopped while a lactose-free and medium-chain triglycerides (MCT)-enriched formula was introduced. When aged 4.9 months, SLC25A13 genetic analysis in our hospital unveiled a homozygote of the c.852_855del4 mutation () and the diagnosis of NICCD was hence made. Thereafter, besides feeding with the therapeutic formula, supplemental foods rich in protein were encouraged. As a result, her liver function indices got improved gradually and returned to normal by age 10.2 months. However, the hypercholanemia was refractory, with total bile acid (TBA) levels fluctuating from 27.6 µmol/L to 340.2 µmol/L (reference range: 0–10 µmol/L) (). After the age 2 years, the patient showed a fondness for foods rich in protein and fat while an aversion to carbohydrate-rich diets.\nAs the first product of a non-consanguineous couple, the child was delivered spontaneously at the gestational age of 38 weeks and 3 days after an uneventful pregnancy, with a birth weight of 3.0 kg and body length 50 cm. The parents were healthy, and there was no family history of any genetic or infectious diseases.\nPhysical examination revealed a body temperature (T) 36.5°C, heart rate (HR) 115 beats/min (bpm), respiratory rate (RR) 20 bpm, weight (WT) 18 kg, height 107.0 cm. No jaundice was observed in the skin and sclera. The lungs were clear. No murmurs or abnormal heart sounds were heard. There was no abdominal distention, and the liver and spleen were not enlarged. Physiological reflexes were normal and no pathological reflexes could be found on nervous system examination. The extremities were warm, and the distal perfusion was excellent.\nLaboratory investigation showed otherwise normal biochemical indices but a TBA level of 48.7 µmol/L. In view of the intractable hypercholanemia, NTCP deficiency was highly suspected, and SLC10A1 genetic analysis was performed. As a result, the patient was a homozygote, while the parents, carriers, of the reportedly pathogenic variant c.800C > T(p.Ser267Phe)(). NTCP deficiency was thus definitely diagnosed. No specific therapy was given but close clinic follow-up was underway.

Patient 1. A 2-years-old female infant was referred to the First Affiliated Hospital, Jinan University, due to elevated serum total bile acids (TBA) discovered for 21 months. At the age 3 months, she was admitted to Women and Children's Hospital of Quanzhou because of jaundice for 2 months. Laboratory test revealed that the serum levels of TBA, direct bilirubin (DBIL), aspartate transaminase (AST) and alanine transaminase (ALT) were all elevated (Table ), and she was thus diagnosed to have cholestatic liver disease. After being treated with intravenous reduced glutathione and ademetionine-1,4-butanedisulfonate for 9 days, which were commonly used in cholestatic patients with elevated alanine transaminase levels, her jaundice was alleviated, but the liver function indices remained abnormal (Table ). Then oral ursodesoxycholic acid was given and she was discharged at the age 3.3 months. During the subsequent follow-up over 20 months, she showed normal anthropometric and neurobehavioral development without abnormal appearance, and her cholestasis resolved completely since the age 7 months. However, persistently raised TBA levels were observed on repeated biochemical analyses (Table ). So she was referred to our hospital for further investigation and management when aged 2 years.\nThe patient was the elder sister of two monochorionic diamniotic twins who was delivered by cesarean section at the gestation age of 37 weeks and 2 days with the birth weight 2.25 kg and body length 45.0 cm. Her father is a hepatitis B virus (HBV) carrier who was clinically healthy but with slightly elevated serum TBA level on biochemistry analysis, and her mother was physically and biochemically healthy (Table ). There was no family history of any genetic disease.\nPhysical examination revealed a body weight of 12.0 kg, height 83.5 cm and head circumference 46.0 cm. No jaundice was observed in the skin and sclera. No stridor, crackles or crepitus was heard in the two lungs, and the heart sound was normal without any murmurs. There was no abdominal distention, and the liver and spleen were non-palpable. Physiological reflexes were normal and no pathological reflexes could be found on nervous system examination. On biochemical analysis, the TBA level reached 173.8 μmol/L (0–10 μmol/L) as other indices were normal (Table ).

Write a detailed clinical case vignette based on the following key phrases: Liver function abnormalities, Genetic disorders, Bile acid metabolism

Patient 3 was a 1-year-and-2-month-old female referred to our hospital because of abnormal liver function discovered for 12.7 months. At the age 1.3 months, she went through a liver function test because of prolonged jaundice for 1 month, which showed raised levels of AST, GGT, ALP, TBIL, DBIL, and IBIL (). When aged 1.8 months, her TBA level was found to be as high as 172.0 µmol/L besides the cholestatic alterations (), and the MS-MS analysis revealed increased levels of tyrosine, citrulline, and methionine while large quantities of urinary 4HPPV and 4HPL were detected on GC-MS analysis. NICCD was consequently suspected, and breast-feeding was stopped while a lactose-free and MCT-enriched formula was suggested. Following that, her cholestatic jaundice got alleviated rapidly and the laboratory alterations recovered to normal levels by the age 5 months, while the hypercholanemia was intractable, even beyond 1 year of age ().\nAs the first child of a non-consanguineous couple, the infant was delivered by cesarean section at the gestation age of 38 weeks and 2 days with the birth weight 2,750 g. Her father was clinically healthy with an elevated serum TBA level of 21.1 µmol/L (0–10 µmol/L), and her mother was physically and biochemically healthy (). There was no family history of any genetic diseases.\nPhysical examination at referral revealed a body weight 10.1 kg, length 80 cm and head circumference 46 cm. No jaundice was observed in the skin and sclera. Examinations of the heart, the lungs, the abdomen, and nervous system were all normal.\nBiochemical test at referral revealed a TBA level 50.9 µmol/L with otherwise normal indices (). On genetic analysis, the patient was a compound heterozygote of the SLC25A13 mutations c.852_855del4 and c.1638_1660dup, which was inherited from the father and mother, respectively (); moreover, the patient and her father were both homozygous for the SLC10A1 variant c.800C > T (p.Ser267Phe), while her mother was a carrier (). Hence, citrin deficiency and NTCP deficiency were definitely diagnosed for the infant. No specific therapy was given, and his TBA level tended downward to 25.6 µmol/L at the age of 3 years and 4 months (), still remaining beyond the upper limit. The patient also had a fondness of protein-rich foods while an aversion to carbohydrate-rich foods from the age 1 year.\nThe molecular findings above were further confirmed by Sanger sequencing () and illustrated as family tree diagrams (). The clinical and molecular features of all the 3 patients were summarized in .

A 7-month-old female infant was referred to our hospital due to prolonged jaundice for approximately 4 months and growth retardation for 1.5 months. Her jaundice (yellow skin and sclera) drew the attention of her parents at the age of 3.3 months. A liver function test at the local hospital revealed elevated cholestatic indices, including gamma-glutamyl transpeptidase (GGT), direct bilirubin (Dbil) and total bile acid (TBA) (). Due to the prolonged jaundice and unresolved laboratory abnormalities, the infant was referred to another hospital at the age of 4 months, where magnetic resonance cholangiopancreatography revealed the dilatation of common hepatic and bile ducts. Laparoscopy was thus performed when the infant was aged 4.5 months, and an intraoperative cholangiography displayed biliary tree dilatation and filling defect in the common bile duct, along with an accessory hepatic duct (AHD) joining the cystic duct (). A cholecystectomy was subsequently performed, an intrabiliary thick plug in the color of dark green was removed, and bile duct irrigation and choledochostomy with T-tube drainage was carried out. Pathological analysis of the plug confirmed the diagnosis of inspissated bile syndrome (IBS). Thereafter, the infant’s jaundice subsided and the laboratory indices gradually improved (); the infant was discharged at the age of 5 months. Half a month later, nevertheless, a physical examination revealed that her body weight was 5.34 kg (−3.6 SD), her length was 59 cm (−3.2 SD) and her head circumference was 39 cm (−2.5 SD). Another anthropometric test at the age of 6 months revealed a weight of 6.0 kg (−2.5 SD) and a length of 62.0 cm (−2.2 SD). The growth retardation continued in the following month, and the infant was referred to our hospital at the age of 7 months for further evaluation, following the removal of the drainage T-tube.\nThe infant was born to a non-consanguineous couple after 37 weeks of uneventful gestation with a birth weight of 2.25 kg. On the first day after birth, the infant was admitted to hospital due to vomiting and respiratory distress. Contrast imaging of the upper digestive tract revealed the existence of esophageal atresia (EA) (), which was then resolved by a gastroesophagostomy under general anesthesia. The couple had experienced 2 pregnancies prior to this one, but both were aborted in the first trimester. Both parents appeared healthy, without any clinical symptoms or signs of CTLN2. There was no known family history of any genetic disease.\nPhysical examination at referral revealed a weight of 6.25 kg (−2.6 SD), a length of 63.0 cm (−3.3 SD) and a head circumference of 42 cm (−1.0 SD). There was no dysmorphic appearance, only a slightly chubby face. There was no evidence of jaundice (yellow skin and sclera) and there were no visible petechiae or ecchymoses. No pallor or cyanosis of the lips were observed. There was no tachypnea or dyspnea, and no stridor, wheezes, crackles or crepitus could be heard on auscultation of the both lungs. The heart sounds were normal without audible murmurs or arrhythmia. Upon abdominal inspection, no dilated veins or abdominal distention were observed. The liver was palpated with a soft edge 2 cm below the right costal margin in the mid-clavicular line. Her spleen was not palpable. A neurological examination revealed slightly reduced muscle tone. There was no neck stiffness, knee reflex was normal and there was no positivity for Brudzinski’s or Kernig’s sign.\nFollowing biochemical analysis, no abnormal liver function index was observed, although the serum GGT level was elevated, suggesting the existence of cholestasis, as shown in . Taking into consideration her prolonged jaundice, growth retardation and chubby face, and the 2 first-trimester miscarriages of her mother, SLC25A13 gene analysis was performed on the family to evaluate the possibility of a diagnosis of CD. A lactose-free and MCT-enriched therapeutic formula was subsequently introduced, while a diet rich in protein and lipids was also encouraged. A clinical following-up 4 months later revealed that the weight of the infant was 7.9 kg (−1.6 SD), her length was 70 cm (−1.5 SD) and her head circumference was 44 cm (−0.8 SD), along with a marked improvement (complete recovery) of the cholestatic indices, GGT, TBA and Dbil ().

Write a detailed clinical case vignette based on the following key phrases: Liver function abnormalities, Genetic disorders, Bile acid metabolism

Patient 3 was a 1-year-and-2-month-old female referred to our hospital because of abnormal liver function discovered for 12.7 months. At the age 1.3 months, she went through a liver function test because of prolonged jaundice for 1 month, which showed raised levels of AST, GGT, ALP, TBIL, DBIL, and IBIL (). When aged 1.8 months, her TBA level was found to be as high as 172.0 µmol/L besides the cholestatic alterations (), and the MS-MS analysis revealed increased levels of tyrosine, citrulline, and methionine while large quantities of urinary 4HPPV and 4HPL were detected on GC-MS analysis. NICCD was consequently suspected, and breast-feeding was stopped while a lactose-free and MCT-enriched formula was suggested. Following that, her cholestatic jaundice got alleviated rapidly and the laboratory alterations recovered to normal levels by the age 5 months, while the hypercholanemia was intractable, even beyond 1 year of age ().\nAs the first child of a non-consanguineous couple, the infant was delivered by cesarean section at the gestation age of 38 weeks and 2 days with the birth weight 2,750 g. Her father was clinically healthy with an elevated serum TBA level of 21.1 µmol/L (0–10 µmol/L), and her mother was physically and biochemically healthy (). There was no family history of any genetic diseases.\nPhysical examination at referral revealed a body weight 10.1 kg, length 80 cm and head circumference 46 cm. No jaundice was observed in the skin and sclera. Examinations of the heart, the lungs, the abdomen, and nervous system were all normal.\nBiochemical test at referral revealed a TBA level 50.9 µmol/L with otherwise normal indices (). On genetic analysis, the patient was a compound heterozygote of the SLC25A13 mutations c.852_855del4 and c.1638_1660dup, which was inherited from the father and mother, respectively (); moreover, the patient and her father were both homozygous for the SLC10A1 variant c.800C > T (p.Ser267Phe), while her mother was a carrier (). Hence, citrin deficiency and NTCP deficiency were definitely diagnosed for the infant. No specific therapy was given, and his TBA level tended downward to 25.6 µmol/L at the age of 3 years and 4 months (), still remaining beyond the upper limit. The patient also had a fondness of protein-rich foods while an aversion to carbohydrate-rich foods from the age 1 year.\nThe molecular findings above were further confirmed by Sanger sequencing () and illustrated as family tree diagrams (). The clinical and molecular features of all the 3 patients were summarized in .

Patient 2. A 5-day-old male infant was admitted to our Neonatal Section because of jaundice for 3 days. Mild jaundice appeared at age 2 days. At the 5th day after birth, the total bilirubin increased to 310.1 μmol/L. Then the infant was referred to our clinic, where a laboratory test revealed elevated TBA as well as indirect hyperbilirubinemia (Table ), and thus the infant was admitted for further management. As the first child of a non-consanguineous couple, the patient was delivered vaginally at the gestational age of 37 weeks with the birth weight 3050 g. The parents were both healthy. Family history of any genetic disease was denied.\nOn physical examination, the body weight was 2910 g, with T 36.2°C, HR 130 beats/min, and RR 43 breaths/min. Jaundiced skin and sclera were observed. The lungs were clear on auscultation, and no abnormal heart sound or murmur was heard. There was no abdominal distention, and the liver and spleen were not palpable. Primitive reflexes were normal and no pathological reflexes could be found on nervous system examination.\nThe patient underwent phototherapy for 3 days. As a result, his jaundice subsided, and he was discharged at age 9 days. No special treatment was given thereafter, and the jaundice did not reappear. However, his serum TBA levels kept high in the following 1 month, and hence SLC10A1 analysis was performed at age 33 days to evaluate the possibility of NTCP deficiency. On Sanger sequencing of the UGT1A1 gene, no pathogenic variant was detected but three benign SNPs in the 3ʹ UTR, i.e. rs10929303, rs1042640 and rs8330 [].

Write a detailed clinical case vignette based on the following key phrases: Liver function abnormalities, Genetic disorders, Bile acid metabolism

Patient 3 was a 1-year-and-2-month-old female referred to our hospital because of abnormal liver function discovered for 12.7 months. At the age 1.3 months, she went through a liver function test because of prolonged jaundice for 1 month, which showed raised levels of AST, GGT, ALP, TBIL, DBIL, and IBIL (). When aged 1.8 months, her TBA level was found to be as high as 172.0 µmol/L besides the cholestatic alterations (), and the MS-MS analysis revealed increased levels of tyrosine, citrulline, and methionine while large quantities of urinary 4HPPV and 4HPL were detected on GC-MS analysis. NICCD was consequently suspected, and breast-feeding was stopped while a lactose-free and MCT-enriched formula was suggested. Following that, her cholestatic jaundice got alleviated rapidly and the laboratory alterations recovered to normal levels by the age 5 months, while the hypercholanemia was intractable, even beyond 1 year of age ().\nAs the first child of a non-consanguineous couple, the infant was delivered by cesarean section at the gestation age of 38 weeks and 2 days with the birth weight 2,750 g. Her father was clinically healthy with an elevated serum TBA level of 21.1 µmol/L (0–10 µmol/L), and her mother was physically and biochemically healthy (). There was no family history of any genetic diseases.\nPhysical examination at referral revealed a body weight 10.1 kg, length 80 cm and head circumference 46 cm. No jaundice was observed in the skin and sclera. Examinations of the heart, the lungs, the abdomen, and nervous system were all normal.\nBiochemical test at referral revealed a TBA level 50.9 µmol/L with otherwise normal indices (). On genetic analysis, the patient was a compound heterozygote of the SLC25A13 mutations c.852_855del4 and c.1638_1660dup, which was inherited from the father and mother, respectively (); moreover, the patient and her father were both homozygous for the SLC10A1 variant c.800C > T (p.Ser267Phe), while her mother was a carrier (). Hence, citrin deficiency and NTCP deficiency were definitely diagnosed for the infant. No specific therapy was given, and his TBA level tended downward to 25.6 µmol/L at the age of 3 years and 4 months (), still remaining beyond the upper limit. The patient also had a fondness of protein-rich foods while an aversion to carbohydrate-rich foods from the age 1 year.\nThe molecular findings above were further confirmed by Sanger sequencing () and illustrated as family tree diagrams (). The clinical and molecular features of all the 3 patients were summarized in .

Patient 2 was a 1-year-and-1-month-old male visiting our clinic due to hypercholanemia discovered for 11 months. At the age 2 months, he was referred to a local hospital because of prolonged jaundice for about 1 month. On biochemistry analysis, elevated serum levels of AST, GGT, ALP, TBIL, DBIL, and IBIL, together with decreased level of albumin were detected, and notably, the TBA level reached 268.7 µmol/L (). Subsequent urinary GC-MS analysis detected elevated 4-hydroxyphenylpyruvate (4-HPPV) and 4HPL, while raised levels of citrulline, methionine, and threonine were detected on MS-MS analysis of blood sample. When aged 2.1 months, the infant undertook SLC25A13 analysis in our hospital, and proved to be a homozygote of the c.852_855del4 mutation (), and the diagnosis of NICCD was thus made. Then breast-feeding was stopped and a lactose-free and MCT-enriched formula was given. Then his jaundice disappeared rapidly, and serum bilirubin levels returned to normal at his age 5.5 months (). However, the hypercholanemia persisted, even beyond 1 year of age (). No steatorrhea or acholic stool was observed during the course of the disease.\nAs the first child of a non-consanguineous couple, the patient was delivered vaginally at the gestational age of 37 weeks and 4 days with the birth weight 2700 g. The Apgar score was 9 points at 1 min and 10 points at 5 min after umbilical ligation. Parents were both hepatitis B virus (HBV) carriers, who were apparently healthy but with slightly raised serum TBA levels (). Family history of any genetic diseases was denied.\nPhysical examination revealed a body T 36.6°C, weight 10.5 kg, HR 126 bpm, and RR 32 bpm. No jaundiced skin and sclera was observed. On auscultation, no abnormal sounds were heard on the lungs and heart. There was no abdominal distention, and the liver and spleen were non-palpable. Primitive reflexes were normal and pathological reflexes could not be found on nervous system examination.\nLaboratory test at visiting revealed a serum TBA level of 234.5 µmol/L and otherwise normal indices. SLC10A1 genetic analysis demonstrated that the patient was a homozygote, and his parents, carriers, of the variant c.800C > T (p.Ser267Phe) (). The diagnosis of NTCP deficiency was thus made. No specific therapy was given but clinic follow up was suggested. His serum TBA level was 148 µmol/L () when aged 1 year and 6 months, and a fondness for low-carbohydrate and high-protein foods was noticed since the age of 1 year.

Write a detailed clinical case vignette based on the following key phrases: Liver function abnormalities, Genetic disorders, Bile acid metabolism

An 18.5-year-old female was presented to the outpatient clinic due to overweight. Her height was 166.1 cm, her weight was 80.1 kg, and her body mass index (BMI) was 29.0 kg/m2. No clinical signs of hyperandrogenism or hypercortisolism were observed. The skin was normal; however, striae cutis distensae were seen. Neither hirsutism nor acanthosis nigricans was present. No indication of ichthyosis was noted. Pubertal development was complete, with breast stage B5, pubic hair stage PH5, menstrual periods were regular. Blood pressure was within the norm, at 125/80 mm Hg.\nThe patient fulfilled only two criteria for metabolic syndrome in adolescence by having disturbed glucose metabolism and abdominal obesity. Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) was increased to 6.9; oral glucose tolerance was pathological (2 h glucose concentration 165 mg/dl). Serum concentrations of high-density lipoprotein (HDL)-cholesterol (60 mg/dl) and triglycerides (108 mg/dl) were within the reference range, while cholesterol (232 mg/dl) and low-density lipoprotein (LDL)-cholesterol (186 mg/dl) were increased. The patient underwent a relatively successful lifestyle intervention, which enabled a stabilization of her BMI and a normalization of her oral glucose tolerance within 6 months.\nRoutine analysis of adrenal hormones revealed an extremely high serum DHEAS level, at 7,546 ng/ml (reference < 4,000; ). A second blood sample confirmed the DHEAS excess, with even a higher serum level, at 8,835 ng/ml. In contrast, serum DHEA was in the normal range, at 443 ng/dl (reference < 750). Serum ACTH (4.8 pmol/L), cortisol (22.7 μg/dl), androstenedione (10 nmol/L), 17-OH progesterone (70 ng/dl), testosterone (28 ng/dl), luteinizing hormone (LH; 5.7 UI/L), follicle-stimulating hormone (FSH; 1.7 IU/L), as well as thyroid-stimulating hormone (TSH; 1.57 mIU/L), and free thyroxine (fT4; 14 pmol/L) levels were all within the normal range.\nThe serum steroid sulfatome was analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The high DHEAS serum level was confirmed. Interestingly, with the exception of cholesterol sulfate, several other sulfated steroids were found to be above the reference range, namely, pregnenolone sulfate, 17-hydroxypregnenolone sulfate, 16-α-hydroxy-DHEAS, androstenediol-3-sulfate, androsterone sulfate, and epiandrosterone sulfate (). In addition, the urinary steroid metabolome was delineated by gas chromatography-mass spectrometry (GC-MS) in a 24 h urinary sample. It revealed excessive excretion of DHEAS metabolites at 200% of the upper limit of the reference interval. Urinary analysis excluded any known enzyme defect of the adrenal steroid synthesis.\nFor exclusion of an autonomous hormone secretion by an adrenal or an ovarian tumor, administration of 0.5 mg dexamethasone four times daily on four consecutive days was performed which resulted in an efficient suppression of DHEAS and DHEA as well as their urinary metabolites. On day 5, the DHEAS level decreased to 1,199 ng/ml (13.6% of baseline; reference < 47.2%) and the DHEA level to 144 ng/dl (32% of baseline; reference < 38.9%) (). In addition, urinary cortisol metabolites were sufficiently suppressed during the dexamethasone test. Ultrasound and MRI scans of the adrenal glands and the ovaries were normal. No further deterioration in the patient's hormonal investigations was noted during the 4 year course of observation.\nFollowing the hypothesis that the high DHEAS level was likely to be hereditary, we sequenced the STS gene, which is responsible for the hydrolysis of aryl and alkyl steroid sulfates and catalyzes the conversion of DHEAS to DHEA (). Sequence analysis revealed a heterozygous single-base substitution (g.117217G>T) that results in a nonsense mutation at codon 173 (p.G173X). This mutation predicts a truncation of the carboxyl region of the STS enzyme that is implicated in substrate binding. The mutant allele contained two further variants within the fifth exon: a silent mutation (g.117309C>A) at codon 203 C → A (leucine), and a missense mutation at codon 464 G → T, which resulted in substitution of methionine for isoleucine (g.117465G>T). This nonsense mutation is not present in the Exome Variant Server. At 19 bp upstream in the genomic sequence of exon 10, we identified another C → T transition (g.207619C>T). The nonsense mutation p.G173X found in the patient was de novo as demonstrated by allele-specific amplification of the wild-type (wt) and mutant sequences (mut) of both parents' DNA samples. No partial gene deletion of the presumably intact allele outside exon 5 was detected by multiplex ligation-dependent probe amplification.\nBiological activity of STS was measured in the patient's blood leukocytes after addition of 1,2,6,7-3H-DHEAS. In our experimental setting, ~7 nmol DHEA was produced by 1 × 106 leukocytes per 4 h. The mean (SD) STS activity detected in patient's leukocytes was 107% in comparison to those of five healthy age-matched female controls. Therefore, normal hydrolytic activity of STS was revealed in the patient's blood leukocytes.\nNo clear explanation for the high levels of DHEAS connected to the STS gene structure and enzyme activity was found. Therefore, a defect of one or more transporter proteins was suggested (). On the one hand, a reduced steroid sulfate efflux activity in the liver would enhance serum levels; on the other hand, impaired steroid sulfate uptake from the circulation into peripheral target cells or hepatocytes would have the same effect. Prominent candidate efflux transporters were MRP2 and BCRP, both highly expressed at the canalicular membrane of hepatocytes and involved in the hepatobiliary elimination of many drugs and some endogenous substrates such as sulfated steroids (). However, as MRP2 deficiency would typically increase the levels of conjugated bilirubin in the plasma (Dubin–Johnson syndrome) () what was not seen in the patient, BCRP was the only candidate carrier for the efflux site. On the uptake site, several OATP and OAT carriers were on the list. However, as most of them show highly overlapping substrate specificities and redundant expression patterns (e.g., OATP1B1, OATP1B3, and OATP2B1 are expressed in the liver) (), it was supposed that a transport defect of one of these carriers could have been compensated by another member of the same carrier family. Therefore, we decided to select two carriers from the SLC10 carrier family, which are more unique in the sense of substrate specificity and tissue expression and which both show sodium-dependent transport of sulfated steroids (, ). In both carriers, genetic variants or mutations were described before with significantly reduced transport activity, associated with increased plasma levels of their substrates (–). However, as the determination of DHEAS serum levels is not included in standard diagnostics, elevated DHEAS levels may have been overseen in patients with such carrier defects. Using exon-spanning PCR, all exons of the abovementioned membrane transporters were sequenced. There were no relevant variants detected for the SLC10A1 and SLC10A6 genes. Sequence analysis revealed a heterozygous Q141K variant for BCRP. Interestingly, this variant has in its homozygous state previously been associated with reduced efflux transport activity ().

Patient 3 was a 1-year-and-2-month-old female referred to our hospital because of abnormal liver function discovered for 12.7 months. At the age 1.3 months, she went through a liver function test because of prolonged jaundice for 1 month, which showed raised levels of AST, GGT, ALP, TBIL, DBIL, and IBIL (). When aged 1.8 months, her TBA level was found to be as high as 172.0 µmol/L besides the cholestatic alterations (), and the MS-MS analysis revealed increased levels of tyrosine, citrulline, and methionine while large quantities of urinary 4HPPV and 4HPL were detected on GC-MS analysis. NICCD was consequently suspected, and breast-feeding was stopped while a lactose-free and MCT-enriched formula was suggested. Following that, her cholestatic jaundice got alleviated rapidly and the laboratory alterations recovered to normal levels by the age 5 months, while the hypercholanemia was intractable, even beyond 1 year of age ().\nAs the first child of a non-consanguineous couple, the infant was delivered by cesarean section at the gestation age of 38 weeks and 2 days with the birth weight 2,750 g. Her father was clinically healthy with an elevated serum TBA level of 21.1 µmol/L (0–10 µmol/L), and her mother was physically and biochemically healthy (). There was no family history of any genetic diseases.\nPhysical examination at referral revealed a body weight 10.1 kg, length 80 cm and head circumference 46 cm. No jaundice was observed in the skin and sclera. Examinations of the heart, the lungs, the abdomen, and nervous system were all normal.\nBiochemical test at referral revealed a TBA level 50.9 µmol/L with otherwise normal indices (). On genetic analysis, the patient was a compound heterozygote of the SLC25A13 mutations c.852_855del4 and c.1638_1660dup, which was inherited from the father and mother, respectively (); moreover, the patient and her father were both homozygous for the SLC10A1 variant c.800C > T (p.Ser267Phe), while her mother was a carrier (). Hence, citrin deficiency and NTCP deficiency were definitely diagnosed for the infant. No specific therapy was given, and his TBA level tended downward to 25.6 µmol/L at the age of 3 years and 4 months (), still remaining beyond the upper limit. The patient also had a fondness of protein-rich foods while an aversion to carbohydrate-rich foods from the age 1 year.\nThe molecular findings above were further confirmed by Sanger sequencing () and illustrated as family tree diagrams (). The clinical and molecular features of all the 3 patients were summarized in .

Write a detailed clinical case vignette based on the following key phrases: Liver function abnormalities, Genetic disorders, Bile acid metabolism

Patient 3 was a 1-year-and-2-month-old female referred to our hospital because of abnormal liver function discovered for 12.7 months. At the age 1.3 months, she went through a liver function test because of prolonged jaundice for 1 month, which showed raised levels of AST, GGT, ALP, TBIL, DBIL, and IBIL (). When aged 1.8 months, her TBA level was found to be as high as 172.0 µmol/L besides the cholestatic alterations (), and the MS-MS analysis revealed increased levels of tyrosine, citrulline, and methionine while large quantities of urinary 4HPPV and 4HPL were detected on GC-MS analysis. NICCD was consequently suspected, and breast-feeding was stopped while a lactose-free and MCT-enriched formula was suggested. Following that, her cholestatic jaundice got alleviated rapidly and the laboratory alterations recovered to normal levels by the age 5 months, while the hypercholanemia was intractable, even beyond 1 year of age ().\nAs the first child of a non-consanguineous couple, the infant was delivered by cesarean section at the gestation age of 38 weeks and 2 days with the birth weight 2,750 g. Her father was clinically healthy with an elevated serum TBA level of 21.1 µmol/L (0–10 µmol/L), and her mother was physically and biochemically healthy (). There was no family history of any genetic diseases.\nPhysical examination at referral revealed a body weight 10.1 kg, length 80 cm and head circumference 46 cm. No jaundice was observed in the skin and sclera. Examinations of the heart, the lungs, the abdomen, and nervous system were all normal.\nBiochemical test at referral revealed a TBA level 50.9 µmol/L with otherwise normal indices (). On genetic analysis, the patient was a compound heterozygote of the SLC25A13 mutations c.852_855del4 and c.1638_1660dup, which was inherited from the father and mother, respectively (); moreover, the patient and her father were both homozygous for the SLC10A1 variant c.800C > T (p.Ser267Phe), while her mother was a carrier (). Hence, citrin deficiency and NTCP deficiency were definitely diagnosed for the infant. No specific therapy was given, and his TBA level tended downward to 25.6 µmol/L at the age of 3 years and 4 months (), still remaining beyond the upper limit. The patient also had a fondness of protein-rich foods while an aversion to carbohydrate-rich foods from the age 1 year.\nThe molecular findings above were further confirmed by Sanger sequencing () and illustrated as family tree diagrams (). The clinical and molecular features of all the 3 patients were summarized in .

Patient 1 was a 5–year-and-11-month-old female referred to the First Affiliated Hospital, Jinan University due to abnormal liver function discovered for 5 years and 7 months. When aged 4 months, she was admitted to a hospital in Guangzhou due to jaundice for 3 months, where physical examination revealed an enlarged liver 4.0 cm below the right costal margin, and a liver function test revealed elevated serum levels of total bilirubin (TBIL), direct bilirubin (DBIL), indirect bilirubin (IBIL), alanine transaminase (ALT), aspartate transaminase (AST), γ-glutamyl transpeptidase (GGT), and alkaline phosphatase (ALP), indicating cholestatic jaundice (). Blood amino acid spectrum analysis by tandem mass spectrometry (MS-MS) revealed raised citrulline, methionine, arginine, and threonine, while large quantities of galactose, galactitol, galactonate, and 4-hydroxyphenyllactate (4HPL) were detected on urinary gas chromatography-mass spectrometry (GC-MS) analysis. Considering the above clinical and laboratory findings, NICCD was suspected, and breast-feeding was stopped while a lactose-free and medium-chain triglycerides (MCT)-enriched formula was introduced. When aged 4.9 months, SLC25A13 genetic analysis in our hospital unveiled a homozygote of the c.852_855del4 mutation () and the diagnosis of NICCD was hence made. Thereafter, besides feeding with the therapeutic formula, supplemental foods rich in protein were encouraged. As a result, her liver function indices got improved gradually and returned to normal by age 10.2 months. However, the hypercholanemia was refractory, with total bile acid (TBA) levels fluctuating from 27.6 µmol/L to 340.2 µmol/L (reference range: 0–10 µmol/L) (). After the age 2 years, the patient showed a fondness for foods rich in protein and fat while an aversion to carbohydrate-rich diets.\nAs the first product of a non-consanguineous couple, the child was delivered spontaneously at the gestational age of 38 weeks and 3 days after an uneventful pregnancy, with a birth weight of 3.0 kg and body length 50 cm. The parents were healthy, and there was no family history of any genetic or infectious diseases.\nPhysical examination revealed a body temperature (T) 36.5°C, heart rate (HR) 115 beats/min (bpm), respiratory rate (RR) 20 bpm, weight (WT) 18 kg, height 107.0 cm. No jaundice was observed in the skin and sclera. The lungs were clear. No murmurs or abnormal heart sounds were heard. There was no abdominal distention, and the liver and spleen were not enlarged. Physiological reflexes were normal and no pathological reflexes could be found on nervous system examination. The extremities were warm, and the distal perfusion was excellent.\nLaboratory investigation showed otherwise normal biochemical indices but a TBA level of 48.7 µmol/L. In view of the intractable hypercholanemia, NTCP deficiency was highly suspected, and SLC10A1 genetic analysis was performed. As a result, the patient was a homozygote, while the parents, carriers, of the reportedly pathogenic variant c.800C > T(p.Ser267Phe)(). NTCP deficiency was thus definitely diagnosed. No specific therapy was given but close clinic follow-up was underway.

Write a detailed clinical case vignette based on the following key phrases: Liver function abnormalities, Genetic disorders, Bile acid metabolism

A 7-month-old female infant was referred to our hospital due to prolonged jaundice for approximately 4 months and growth retardation for 1.5 months. Her jaundice (yellow skin and sclera) drew the attention of her parents at the age of 3.3 months. A liver function test at the local hospital revealed elevated cholestatic indices, including gamma-glutamyl transpeptidase (GGT), direct bilirubin (Dbil) and total bile acid (TBA) (). Due to the prolonged jaundice and unresolved laboratory abnormalities, the infant was referred to another hospital at the age of 4 months, where magnetic resonance cholangiopancreatography revealed the dilatation of common hepatic and bile ducts. Laparoscopy was thus performed when the infant was aged 4.5 months, and an intraoperative cholangiography displayed biliary tree dilatation and filling defect in the common bile duct, along with an accessory hepatic duct (AHD) joining the cystic duct (). A cholecystectomy was subsequently performed, an intrabiliary thick plug in the color of dark green was removed, and bile duct irrigation and choledochostomy with T-tube drainage was carried out. Pathological analysis of the plug confirmed the diagnosis of inspissated bile syndrome (IBS). Thereafter, the infant’s jaundice subsided and the laboratory indices gradually improved (); the infant was discharged at the age of 5 months. Half a month later, nevertheless, a physical examination revealed that her body weight was 5.34 kg (−3.6 SD), her length was 59 cm (−3.2 SD) and her head circumference was 39 cm (−2.5 SD). Another anthropometric test at the age of 6 months revealed a weight of 6.0 kg (−2.5 SD) and a length of 62.0 cm (−2.2 SD). The growth retardation continued in the following month, and the infant was referred to our hospital at the age of 7 months for further evaluation, following the removal of the drainage T-tube.\nThe infant was born to a non-consanguineous couple after 37 weeks of uneventful gestation with a birth weight of 2.25 kg. On the first day after birth, the infant was admitted to hospital due to vomiting and respiratory distress. Contrast imaging of the upper digestive tract revealed the existence of esophageal atresia (EA) (), which was then resolved by a gastroesophagostomy under general anesthesia. The couple had experienced 2 pregnancies prior to this one, but both were aborted in the first trimester. Both parents appeared healthy, without any clinical symptoms or signs of CTLN2. There was no known family history of any genetic disease.\nPhysical examination at referral revealed a weight of 6.25 kg (−2.6 SD), a length of 63.0 cm (−3.3 SD) and a head circumference of 42 cm (−1.0 SD). There was no dysmorphic appearance, only a slightly chubby face. There was no evidence of jaundice (yellow skin and sclera) and there were no visible petechiae or ecchymoses. No pallor or cyanosis of the lips were observed. There was no tachypnea or dyspnea, and no stridor, wheezes, crackles or crepitus could be heard on auscultation of the both lungs. The heart sounds were normal without audible murmurs or arrhythmia. Upon abdominal inspection, no dilated veins or abdominal distention were observed. The liver was palpated with a soft edge 2 cm below the right costal margin in the mid-clavicular line. Her spleen was not palpable. A neurological examination revealed slightly reduced muscle tone. There was no neck stiffness, knee reflex was normal and there was no positivity for Brudzinski’s or Kernig’s sign.\nFollowing biochemical analysis, no abnormal liver function index was observed, although the serum GGT level was elevated, suggesting the existence of cholestasis, as shown in . Taking into consideration her prolonged jaundice, growth retardation and chubby face, and the 2 first-trimester miscarriages of her mother, SLC25A13 gene analysis was performed on the family to evaluate the possibility of a diagnosis of CD. A lactose-free and MCT-enriched therapeutic formula was subsequently introduced, while a diet rich in protein and lipids was also encouraged. A clinical following-up 4 months later revealed that the weight of the infant was 7.9 kg (−1.6 SD), her length was 70 cm (−1.5 SD) and her head circumference was 44 cm (−0.8 SD), along with a marked improvement (complete recovery) of the cholestatic indices, GGT, TBA and Dbil ().

Patient 2. A 5-day-old male infant was admitted to our Neonatal Section because of jaundice for 3 days. Mild jaundice appeared at age 2 days. At the 5th day after birth, the total bilirubin increased to 310.1 μmol/L. Then the infant was referred to our clinic, where a laboratory test revealed elevated TBA as well as indirect hyperbilirubinemia (Table ), and thus the infant was admitted for further management. As the first child of a non-consanguineous couple, the patient was delivered vaginally at the gestational age of 37 weeks with the birth weight 3050 g. The parents were both healthy. Family history of any genetic disease was denied.\nOn physical examination, the body weight was 2910 g, with T 36.2°C, HR 130 beats/min, and RR 43 breaths/min. Jaundiced skin and sclera were observed. The lungs were clear on auscultation, and no abnormal heart sound or murmur was heard. There was no abdominal distention, and the liver and spleen were not palpable. Primitive reflexes were normal and no pathological reflexes could be found on nervous system examination.\nThe patient underwent phototherapy for 3 days. As a result, his jaundice subsided, and he was discharged at age 9 days. No special treatment was given thereafter, and the jaundice did not reappear. However, his serum TBA levels kept high in the following 1 month, and hence SLC10A1 analysis was performed at age 33 days to evaluate the possibility of NTCP deficiency. On Sanger sequencing of the UGT1A1 gene, no pathogenic variant was detected but three benign SNPs in the 3ʹ UTR, i.e. rs10929303, rs1042640 and rs8330 [].

Write a detailed clinical case vignette based on the following key phrases: Liver function abnormalities, Genetic disorders, Bile acid metabolism

A 7-month-old female infant was referred to our hospital due to prolonged jaundice for approximately 4 months and growth retardation for 1.5 months. Her jaundice (yellow skin and sclera) drew the attention of her parents at the age of 3.3 months. A liver function test at the local hospital revealed elevated cholestatic indices, including gamma-glutamyl transpeptidase (GGT), direct bilirubin (Dbil) and total bile acid (TBA) (). Due to the prolonged jaundice and unresolved laboratory abnormalities, the infant was referred to another hospital at the age of 4 months, where magnetic resonance cholangiopancreatography revealed the dilatation of common hepatic and bile ducts. Laparoscopy was thus performed when the infant was aged 4.5 months, and an intraoperative cholangiography displayed biliary tree dilatation and filling defect in the common bile duct, along with an accessory hepatic duct (AHD) joining the cystic duct (). A cholecystectomy was subsequently performed, an intrabiliary thick plug in the color of dark green was removed, and bile duct irrigation and choledochostomy with T-tube drainage was carried out. Pathological analysis of the plug confirmed the diagnosis of inspissated bile syndrome (IBS). Thereafter, the infant’s jaundice subsided and the laboratory indices gradually improved (); the infant was discharged at the age of 5 months. Half a month later, nevertheless, a physical examination revealed that her body weight was 5.34 kg (−3.6 SD), her length was 59 cm (−3.2 SD) and her head circumference was 39 cm (−2.5 SD). Another anthropometric test at the age of 6 months revealed a weight of 6.0 kg (−2.5 SD) and a length of 62.0 cm (−2.2 SD). The growth retardation continued in the following month, and the infant was referred to our hospital at the age of 7 months for further evaluation, following the removal of the drainage T-tube.\nThe infant was born to a non-consanguineous couple after 37 weeks of uneventful gestation with a birth weight of 2.25 kg. On the first day after birth, the infant was admitted to hospital due to vomiting and respiratory distress. Contrast imaging of the upper digestive tract revealed the existence of esophageal atresia (EA) (), which was then resolved by a gastroesophagostomy under general anesthesia. The couple had experienced 2 pregnancies prior to this one, but both were aborted in the first trimester. Both parents appeared healthy, without any clinical symptoms or signs of CTLN2. There was no known family history of any genetic disease.\nPhysical examination at referral revealed a weight of 6.25 kg (−2.6 SD), a length of 63.0 cm (−3.3 SD) and a head circumference of 42 cm (−1.0 SD). There was no dysmorphic appearance, only a slightly chubby face. There was no evidence of jaundice (yellow skin and sclera) and there were no visible petechiae or ecchymoses. No pallor or cyanosis of the lips were observed. There was no tachypnea or dyspnea, and no stridor, wheezes, crackles or crepitus could be heard on auscultation of the both lungs. The heart sounds were normal without audible murmurs or arrhythmia. Upon abdominal inspection, no dilated veins or abdominal distention were observed. The liver was palpated with a soft edge 2 cm below the right costal margin in the mid-clavicular line. Her spleen was not palpable. A neurological examination revealed slightly reduced muscle tone. There was no neck stiffness, knee reflex was normal and there was no positivity for Brudzinski’s or Kernig’s sign.\nFollowing biochemical analysis, no abnormal liver function index was observed, although the serum GGT level was elevated, suggesting the existence of cholestasis, as shown in . Taking into consideration her prolonged jaundice, growth retardation and chubby face, and the 2 first-trimester miscarriages of her mother, SLC25A13 gene analysis was performed on the family to evaluate the possibility of a diagnosis of CD. A lactose-free and MCT-enriched therapeutic formula was subsequently introduced, while a diet rich in protein and lipids was also encouraged. A clinical following-up 4 months later revealed that the weight of the infant was 7.9 kg (−1.6 SD), her length was 70 cm (−1.5 SD) and her head circumference was 44 cm (−0.8 SD), along with a marked improvement (complete recovery) of the cholestatic indices, GGT, TBA and Dbil ().

Patient 2 was a 1-year-and-1-month-old male visiting our clinic due to hypercholanemia discovered for 11 months. At the age 2 months, he was referred to a local hospital because of prolonged jaundice for about 1 month. On biochemistry analysis, elevated serum levels of AST, GGT, ALP, TBIL, DBIL, and IBIL, together with decreased level of albumin were detected, and notably, the TBA level reached 268.7 µmol/L (). Subsequent urinary GC-MS analysis detected elevated 4-hydroxyphenylpyruvate (4-HPPV) and 4HPL, while raised levels of citrulline, methionine, and threonine were detected on MS-MS analysis of blood sample. When aged 2.1 months, the infant undertook SLC25A13 analysis in our hospital, and proved to be a homozygote of the c.852_855del4 mutation (), and the diagnosis of NICCD was thus made. Then breast-feeding was stopped and a lactose-free and MCT-enriched formula was given. Then his jaundice disappeared rapidly, and serum bilirubin levels returned to normal at his age 5.5 months (). However, the hypercholanemia persisted, even beyond 1 year of age (). No steatorrhea or acholic stool was observed during the course of the disease.\nAs the first child of a non-consanguineous couple, the patient was delivered vaginally at the gestational age of 37 weeks and 4 days with the birth weight 2700 g. The Apgar score was 9 points at 1 min and 10 points at 5 min after umbilical ligation. Parents were both hepatitis B virus (HBV) carriers, who were apparently healthy but with slightly raised serum TBA levels (). Family history of any genetic diseases was denied.\nPhysical examination revealed a body T 36.6°C, weight 10.5 kg, HR 126 bpm, and RR 32 bpm. No jaundiced skin and sclera was observed. On auscultation, no abnormal sounds were heard on the lungs and heart. There was no abdominal distention, and the liver and spleen were non-palpable. Primitive reflexes were normal and pathological reflexes could not be found on nervous system examination.\nLaboratory test at visiting revealed a serum TBA level of 234.5 µmol/L and otherwise normal indices. SLC10A1 genetic analysis demonstrated that the patient was a homozygote, and his parents, carriers, of the variant c.800C > T (p.Ser267Phe) (). The diagnosis of NTCP deficiency was thus made. No specific therapy was given but clinic follow up was suggested. His serum TBA level was 148 µmol/L () when aged 1 year and 6 months, and a fondness for low-carbohydrate and high-protein foods was noticed since the age of 1 year.

Write a detailed clinical case vignette based on the following key phrases: Liver function abnormalities, Genetic disorders, Bile acid metabolism

A 7-month-old female infant was referred to our hospital due to prolonged jaundice for approximately 4 months and growth retardation for 1.5 months. Her jaundice (yellow skin and sclera) drew the attention of her parents at the age of 3.3 months. A liver function test at the local hospital revealed elevated cholestatic indices, including gamma-glutamyl transpeptidase (GGT), direct bilirubin (Dbil) and total bile acid (TBA) (). Due to the prolonged jaundice and unresolved laboratory abnormalities, the infant was referred to another hospital at the age of 4 months, where magnetic resonance cholangiopancreatography revealed the dilatation of common hepatic and bile ducts. Laparoscopy was thus performed when the infant was aged 4.5 months, and an intraoperative cholangiography displayed biliary tree dilatation and filling defect in the common bile duct, along with an accessory hepatic duct (AHD) joining the cystic duct (). A cholecystectomy was subsequently performed, an intrabiliary thick plug in the color of dark green was removed, and bile duct irrigation and choledochostomy with T-tube drainage was carried out. Pathological analysis of the plug confirmed the diagnosis of inspissated bile syndrome (IBS). Thereafter, the infant’s jaundice subsided and the laboratory indices gradually improved (); the infant was discharged at the age of 5 months. Half a month later, nevertheless, a physical examination revealed that her body weight was 5.34 kg (−3.6 SD), her length was 59 cm (−3.2 SD) and her head circumference was 39 cm (−2.5 SD). Another anthropometric test at the age of 6 months revealed a weight of 6.0 kg (−2.5 SD) and a length of 62.0 cm (−2.2 SD). The growth retardation continued in the following month, and the infant was referred to our hospital at the age of 7 months for further evaluation, following the removal of the drainage T-tube.\nThe infant was born to a non-consanguineous couple after 37 weeks of uneventful gestation with a birth weight of 2.25 kg. On the first day after birth, the infant was admitted to hospital due to vomiting and respiratory distress. Contrast imaging of the upper digestive tract revealed the existence of esophageal atresia (EA) (), which was then resolved by a gastroesophagostomy under general anesthesia. The couple had experienced 2 pregnancies prior to this one, but both were aborted in the first trimester. Both parents appeared healthy, without any clinical symptoms or signs of CTLN2. There was no known family history of any genetic disease.\nPhysical examination at referral revealed a weight of 6.25 kg (−2.6 SD), a length of 63.0 cm (−3.3 SD) and a head circumference of 42 cm (−1.0 SD). There was no dysmorphic appearance, only a slightly chubby face. There was no evidence of jaundice (yellow skin and sclera) and there were no visible petechiae or ecchymoses. No pallor or cyanosis of the lips were observed. There was no tachypnea or dyspnea, and no stridor, wheezes, crackles or crepitus could be heard on auscultation of the both lungs. The heart sounds were normal without audible murmurs or arrhythmia. Upon abdominal inspection, no dilated veins or abdominal distention were observed. The liver was palpated with a soft edge 2 cm below the right costal margin in the mid-clavicular line. Her spleen was not palpable. A neurological examination revealed slightly reduced muscle tone. There was no neck stiffness, knee reflex was normal and there was no positivity for Brudzinski’s or Kernig’s sign.\nFollowing biochemical analysis, no abnormal liver function index was observed, although the serum GGT level was elevated, suggesting the existence of cholestasis, as shown in . Taking into consideration her prolonged jaundice, growth retardation and chubby face, and the 2 first-trimester miscarriages of her mother, SLC25A13 gene analysis was performed on the family to evaluate the possibility of a diagnosis of CD. A lactose-free and MCT-enriched therapeutic formula was subsequently introduced, while a diet rich in protein and lipids was also encouraged. A clinical following-up 4 months later revealed that the weight of the infant was 7.9 kg (−1.6 SD), her length was 70 cm (−1.5 SD) and her head circumference was 44 cm (−0.8 SD), along with a marked improvement (complete recovery) of the cholestatic indices, GGT, TBA and Dbil ().

An 18.5-year-old female was presented to the outpatient clinic due to overweight. Her height was 166.1 cm, her weight was 80.1 kg, and her body mass index (BMI) was 29.0 kg/m2. No clinical signs of hyperandrogenism or hypercortisolism were observed. The skin was normal; however, striae cutis distensae were seen. Neither hirsutism nor acanthosis nigricans was present. No indication of ichthyosis was noted. Pubertal development was complete, with breast stage B5, pubic hair stage PH5, menstrual periods were regular. Blood pressure was within the norm, at 125/80 mm Hg.\nThe patient fulfilled only two criteria for metabolic syndrome in adolescence by having disturbed glucose metabolism and abdominal obesity. Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) was increased to 6.9; oral glucose tolerance was pathological (2 h glucose concentration 165 mg/dl). Serum concentrations of high-density lipoprotein (HDL)-cholesterol (60 mg/dl) and triglycerides (108 mg/dl) were within the reference range, while cholesterol (232 mg/dl) and low-density lipoprotein (LDL)-cholesterol (186 mg/dl) were increased. The patient underwent a relatively successful lifestyle intervention, which enabled a stabilization of her BMI and a normalization of her oral glucose tolerance within 6 months.\nRoutine analysis of adrenal hormones revealed an extremely high serum DHEAS level, at 7,546 ng/ml (reference < 4,000; ). A second blood sample confirmed the DHEAS excess, with even a higher serum level, at 8,835 ng/ml. In contrast, serum DHEA was in the normal range, at 443 ng/dl (reference < 750). Serum ACTH (4.8 pmol/L), cortisol (22.7 μg/dl), androstenedione (10 nmol/L), 17-OH progesterone (70 ng/dl), testosterone (28 ng/dl), luteinizing hormone (LH; 5.7 UI/L), follicle-stimulating hormone (FSH; 1.7 IU/L), as well as thyroid-stimulating hormone (TSH; 1.57 mIU/L), and free thyroxine (fT4; 14 pmol/L) levels were all within the normal range.\nThe serum steroid sulfatome was analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The high DHEAS serum level was confirmed. Interestingly, with the exception of cholesterol sulfate, several other sulfated steroids were found to be above the reference range, namely, pregnenolone sulfate, 17-hydroxypregnenolone sulfate, 16-α-hydroxy-DHEAS, androstenediol-3-sulfate, androsterone sulfate, and epiandrosterone sulfate (). In addition, the urinary steroid metabolome was delineated by gas chromatography-mass spectrometry (GC-MS) in a 24 h urinary sample. It revealed excessive excretion of DHEAS metabolites at 200% of the upper limit of the reference interval. Urinary analysis excluded any known enzyme defect of the adrenal steroid synthesis.\nFor exclusion of an autonomous hormone secretion by an adrenal or an ovarian tumor, administration of 0.5 mg dexamethasone four times daily on four consecutive days was performed which resulted in an efficient suppression of DHEAS and DHEA as well as their urinary metabolites. On day 5, the DHEAS level decreased to 1,199 ng/ml (13.6% of baseline; reference < 47.2%) and the DHEA level to 144 ng/dl (32% of baseline; reference < 38.9%) (). In addition, urinary cortisol metabolites were sufficiently suppressed during the dexamethasone test. Ultrasound and MRI scans of the adrenal glands and the ovaries were normal. No further deterioration in the patient's hormonal investigations was noted during the 4 year course of observation.\nFollowing the hypothesis that the high DHEAS level was likely to be hereditary, we sequenced the STS gene, which is responsible for the hydrolysis of aryl and alkyl steroid sulfates and catalyzes the conversion of DHEAS to DHEA (). Sequence analysis revealed a heterozygous single-base substitution (g.117217G>T) that results in a nonsense mutation at codon 173 (p.G173X). This mutation predicts a truncation of the carboxyl region of the STS enzyme that is implicated in substrate binding. The mutant allele contained two further variants within the fifth exon: a silent mutation (g.117309C>A) at codon 203 C → A (leucine), and a missense mutation at codon 464 G → T, which resulted in substitution of methionine for isoleucine (g.117465G>T). This nonsense mutation is not present in the Exome Variant Server. At 19 bp upstream in the genomic sequence of exon 10, we identified another C → T transition (g.207619C>T). The nonsense mutation p.G173X found in the patient was de novo as demonstrated by allele-specific amplification of the wild-type (wt) and mutant sequences (mut) of both parents' DNA samples. No partial gene deletion of the presumably intact allele outside exon 5 was detected by multiplex ligation-dependent probe amplification.\nBiological activity of STS was measured in the patient's blood leukocytes after addition of 1,2,6,7-3H-DHEAS. In our experimental setting, ~7 nmol DHEA was produced by 1 × 106 leukocytes per 4 h. The mean (SD) STS activity detected in patient's leukocytes was 107% in comparison to those of five healthy age-matched female controls. Therefore, normal hydrolytic activity of STS was revealed in the patient's blood leukocytes.\nNo clear explanation for the high levels of DHEAS connected to the STS gene structure and enzyme activity was found. Therefore, a defect of one or more transporter proteins was suggested (). On the one hand, a reduced steroid sulfate efflux activity in the liver would enhance serum levels; on the other hand, impaired steroid sulfate uptake from the circulation into peripheral target cells or hepatocytes would have the same effect. Prominent candidate efflux transporters were MRP2 and BCRP, both highly expressed at the canalicular membrane of hepatocytes and involved in the hepatobiliary elimination of many drugs and some endogenous substrates such as sulfated steroids (). However, as MRP2 deficiency would typically increase the levels of conjugated bilirubin in the plasma (Dubin–Johnson syndrome) () what was not seen in the patient, BCRP was the only candidate carrier for the efflux site. On the uptake site, several OATP and OAT carriers were on the list. However, as most of them show highly overlapping substrate specificities and redundant expression patterns (e.g., OATP1B1, OATP1B3, and OATP2B1 are expressed in the liver) (), it was supposed that a transport defect of one of these carriers could have been compensated by another member of the same carrier family. Therefore, we decided to select two carriers from the SLC10 carrier family, which are more unique in the sense of substrate specificity and tissue expression and which both show sodium-dependent transport of sulfated steroids (, ). In both carriers, genetic variants or mutations were described before with significantly reduced transport activity, associated with increased plasma levels of their substrates (–). However, as the determination of DHEAS serum levels is not included in standard diagnostics, elevated DHEAS levels may have been overseen in patients with such carrier defects. Using exon-spanning PCR, all exons of the abovementioned membrane transporters were sequenced. There were no relevant variants detected for the SLC10A1 and SLC10A6 genes. Sequence analysis revealed a heterozygous Q141K variant for BCRP. Interestingly, this variant has in its homozygous state previously been associated with reduced efflux transport activity ().

Write a detailed clinical case vignette based on the following key phrases: Liver function abnormalities, Genetic disorders, Bile acid metabolism

A 7-month-old female infant was referred to our hospital due to prolonged jaundice for approximately 4 months and growth retardation for 1.5 months. Her jaundice (yellow skin and sclera) drew the attention of her parents at the age of 3.3 months. A liver function test at the local hospital revealed elevated cholestatic indices, including gamma-glutamyl transpeptidase (GGT), direct bilirubin (Dbil) and total bile acid (TBA) (). Due to the prolonged jaundice and unresolved laboratory abnormalities, the infant was referred to another hospital at the age of 4 months, where magnetic resonance cholangiopancreatography revealed the dilatation of common hepatic and bile ducts. Laparoscopy was thus performed when the infant was aged 4.5 months, and an intraoperative cholangiography displayed biliary tree dilatation and filling defect in the common bile duct, along with an accessory hepatic duct (AHD) joining the cystic duct (). A cholecystectomy was subsequently performed, an intrabiliary thick plug in the color of dark green was removed, and bile duct irrigation and choledochostomy with T-tube drainage was carried out. Pathological analysis of the plug confirmed the diagnosis of inspissated bile syndrome (IBS). Thereafter, the infant’s jaundice subsided and the laboratory indices gradually improved (); the infant was discharged at the age of 5 months. Half a month later, nevertheless, a physical examination revealed that her body weight was 5.34 kg (−3.6 SD), her length was 59 cm (−3.2 SD) and her head circumference was 39 cm (−2.5 SD). Another anthropometric test at the age of 6 months revealed a weight of 6.0 kg (−2.5 SD) and a length of 62.0 cm (−2.2 SD). The growth retardation continued in the following month, and the infant was referred to our hospital at the age of 7 months for further evaluation, following the removal of the drainage T-tube.\nThe infant was born to a non-consanguineous couple after 37 weeks of uneventful gestation with a birth weight of 2.25 kg. On the first day after birth, the infant was admitted to hospital due to vomiting and respiratory distress. Contrast imaging of the upper digestive tract revealed the existence of esophageal atresia (EA) (), which was then resolved by a gastroesophagostomy under general anesthesia. The couple had experienced 2 pregnancies prior to this one, but both were aborted in the first trimester. Both parents appeared healthy, without any clinical symptoms or signs of CTLN2. There was no known family history of any genetic disease.\nPhysical examination at referral revealed a weight of 6.25 kg (−2.6 SD), a length of 63.0 cm (−3.3 SD) and a head circumference of 42 cm (−1.0 SD). There was no dysmorphic appearance, only a slightly chubby face. There was no evidence of jaundice (yellow skin and sclera) and there were no visible petechiae or ecchymoses. No pallor or cyanosis of the lips were observed. There was no tachypnea or dyspnea, and no stridor, wheezes, crackles or crepitus could be heard on auscultation of the both lungs. The heart sounds were normal without audible murmurs or arrhythmia. Upon abdominal inspection, no dilated veins or abdominal distention were observed. The liver was palpated with a soft edge 2 cm below the right costal margin in the mid-clavicular line. Her spleen was not palpable. A neurological examination revealed slightly reduced muscle tone. There was no neck stiffness, knee reflex was normal and there was no positivity for Brudzinski’s or Kernig’s sign.\nFollowing biochemical analysis, no abnormal liver function index was observed, although the serum GGT level was elevated, suggesting the existence of cholestasis, as shown in . Taking into consideration her prolonged jaundice, growth retardation and chubby face, and the 2 first-trimester miscarriages of her mother, SLC25A13 gene analysis was performed on the family to evaluate the possibility of a diagnosis of CD. A lactose-free and MCT-enriched therapeutic formula was subsequently introduced, while a diet rich in protein and lipids was also encouraged. A clinical following-up 4 months later revealed that the weight of the infant was 7.9 kg (−1.6 SD), her length was 70 cm (−1.5 SD) and her head circumference was 44 cm (−0.8 SD), along with a marked improvement (complete recovery) of the cholestatic indices, GGT, TBA and Dbil ().

Patient 1 was a 5–year-and-11-month-old female referred to the First Affiliated Hospital, Jinan University due to abnormal liver function discovered for 5 years and 7 months. When aged 4 months, she was admitted to a hospital in Guangzhou due to jaundice for 3 months, where physical examination revealed an enlarged liver 4.0 cm below the right costal margin, and a liver function test revealed elevated serum levels of total bilirubin (TBIL), direct bilirubin (DBIL), indirect bilirubin (IBIL), alanine transaminase (ALT), aspartate transaminase (AST), γ-glutamyl transpeptidase (GGT), and alkaline phosphatase (ALP), indicating cholestatic jaundice (). Blood amino acid spectrum analysis by tandem mass spectrometry (MS-MS) revealed raised citrulline, methionine, arginine, and threonine, while large quantities of galactose, galactitol, galactonate, and 4-hydroxyphenyllactate (4HPL) were detected on urinary gas chromatography-mass spectrometry (GC-MS) analysis. Considering the above clinical and laboratory findings, NICCD was suspected, and breast-feeding was stopped while a lactose-free and medium-chain triglycerides (MCT)-enriched formula was introduced. When aged 4.9 months, SLC25A13 genetic analysis in our hospital unveiled a homozygote of the c.852_855del4 mutation () and the diagnosis of NICCD was hence made. Thereafter, besides feeding with the therapeutic formula, supplemental foods rich in protein were encouraged. As a result, her liver function indices got improved gradually and returned to normal by age 10.2 months. However, the hypercholanemia was refractory, with total bile acid (TBA) levels fluctuating from 27.6 µmol/L to 340.2 µmol/L (reference range: 0–10 µmol/L) (). After the age 2 years, the patient showed a fondness for foods rich in protein and fat while an aversion to carbohydrate-rich diets.\nAs the first product of a non-consanguineous couple, the child was delivered spontaneously at the gestational age of 38 weeks and 3 days after an uneventful pregnancy, with a birth weight of 3.0 kg and body length 50 cm. The parents were healthy, and there was no family history of any genetic or infectious diseases.\nPhysical examination revealed a body temperature (T) 36.5°C, heart rate (HR) 115 beats/min (bpm), respiratory rate (RR) 20 bpm, weight (WT) 18 kg, height 107.0 cm. No jaundice was observed in the skin and sclera. The lungs were clear. No murmurs or abnormal heart sounds were heard. There was no abdominal distention, and the liver and spleen were not enlarged. Physiological reflexes were normal and no pathological reflexes could be found on nervous system examination. The extremities were warm, and the distal perfusion was excellent.\nLaboratory investigation showed otherwise normal biochemical indices but a TBA level of 48.7 µmol/L. In view of the intractable hypercholanemia, NTCP deficiency was highly suspected, and SLC10A1 genetic analysis was performed. As a result, the patient was a homozygote, while the parents, carriers, of the reportedly pathogenic variant c.800C > T(p.Ser267Phe)(). NTCP deficiency was thus definitely diagnosed. No specific therapy was given but close clinic follow-up was underway.

Write a detailed clinical case vignette based on the following key phrases: Liver function abnormalities, Genetic disorders, Bile acid metabolism

Patient 2 was a 1-year-and-1-month-old male visiting our clinic due to hypercholanemia discovered for 11 months. At the age 2 months, he was referred to a local hospital because of prolonged jaundice for about 1 month. On biochemistry analysis, elevated serum levels of AST, GGT, ALP, TBIL, DBIL, and IBIL, together with decreased level of albumin were detected, and notably, the TBA level reached 268.7 µmol/L (). Subsequent urinary GC-MS analysis detected elevated 4-hydroxyphenylpyruvate (4-HPPV) and 4HPL, while raised levels of citrulline, methionine, and threonine were detected on MS-MS analysis of blood sample. When aged 2.1 months, the infant undertook SLC25A13 analysis in our hospital, and proved to be a homozygote of the c.852_855del4 mutation (), and the diagnosis of NICCD was thus made. Then breast-feeding was stopped and a lactose-free and MCT-enriched formula was given. Then his jaundice disappeared rapidly, and serum bilirubin levels returned to normal at his age 5.5 months (). However, the hypercholanemia persisted, even beyond 1 year of age (). No steatorrhea or acholic stool was observed during the course of the disease.\nAs the first child of a non-consanguineous couple, the patient was delivered vaginally at the gestational age of 37 weeks and 4 days with the birth weight 2700 g. The Apgar score was 9 points at 1 min and 10 points at 5 min after umbilical ligation. Parents were both hepatitis B virus (HBV) carriers, who were apparently healthy but with slightly raised serum TBA levels (). Family history of any genetic diseases was denied.\nPhysical examination revealed a body T 36.6°C, weight 10.5 kg, HR 126 bpm, and RR 32 bpm. No jaundiced skin and sclera was observed. On auscultation, no abnormal sounds were heard on the lungs and heart. There was no abdominal distention, and the liver and spleen were non-palpable. Primitive reflexes were normal and pathological reflexes could not be found on nervous system examination.\nLaboratory test at visiting revealed a serum TBA level of 234.5 µmol/L and otherwise normal indices. SLC10A1 genetic analysis demonstrated that the patient was a homozygote, and his parents, carriers, of the variant c.800C > T (p.Ser267Phe) (). The diagnosis of NTCP deficiency was thus made. No specific therapy was given but clinic follow up was suggested. His serum TBA level was 148 µmol/L () when aged 1 year and 6 months, and a fondness for low-carbohydrate and high-protein foods was noticed since the age of 1 year.

Patient 2. A 5-day-old male infant was admitted to our Neonatal Section because of jaundice for 3 days. Mild jaundice appeared at age 2 days. At the 5th day after birth, the total bilirubin increased to 310.1 μmol/L. Then the infant was referred to our clinic, where a laboratory test revealed elevated TBA as well as indirect hyperbilirubinemia (Table ), and thus the infant was admitted for further management. As the first child of a non-consanguineous couple, the patient was delivered vaginally at the gestational age of 37 weeks with the birth weight 3050 g. The parents were both healthy. Family history of any genetic disease was denied.\nOn physical examination, the body weight was 2910 g, with T 36.2°C, HR 130 beats/min, and RR 43 breaths/min. Jaundiced skin and sclera were observed. The lungs were clear on auscultation, and no abnormal heart sound or murmur was heard. There was no abdominal distention, and the liver and spleen were not palpable. Primitive reflexes were normal and no pathological reflexes could be found on nervous system examination.\nThe patient underwent phototherapy for 3 days. As a result, his jaundice subsided, and he was discharged at age 9 days. No special treatment was given thereafter, and the jaundice did not reappear. However, his serum TBA levels kept high in the following 1 month, and hence SLC10A1 analysis was performed at age 33 days to evaluate the possibility of NTCP deficiency. On Sanger sequencing of the UGT1A1 gene, no pathogenic variant was detected but three benign SNPs in the 3ʹ UTR, i.e. rs10929303, rs1042640 and rs8330 [].

Write a detailed clinical case vignette based on the following key phrases: Liver function abnormalities, Genetic disorders, Bile acid metabolism

An 18.5-year-old female was presented to the outpatient clinic due to overweight. Her height was 166.1 cm, her weight was 80.1 kg, and her body mass index (BMI) was 29.0 kg/m2. No clinical signs of hyperandrogenism or hypercortisolism were observed. The skin was normal; however, striae cutis distensae were seen. Neither hirsutism nor acanthosis nigricans was present. No indication of ichthyosis was noted. Pubertal development was complete, with breast stage B5, pubic hair stage PH5, menstrual periods were regular. Blood pressure was within the norm, at 125/80 mm Hg.\nThe patient fulfilled only two criteria for metabolic syndrome in adolescence by having disturbed glucose metabolism and abdominal obesity. Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) was increased to 6.9; oral glucose tolerance was pathological (2 h glucose concentration 165 mg/dl). Serum concentrations of high-density lipoprotein (HDL)-cholesterol (60 mg/dl) and triglycerides (108 mg/dl) were within the reference range, while cholesterol (232 mg/dl) and low-density lipoprotein (LDL)-cholesterol (186 mg/dl) were increased. The patient underwent a relatively successful lifestyle intervention, which enabled a stabilization of her BMI and a normalization of her oral glucose tolerance within 6 months.\nRoutine analysis of adrenal hormones revealed an extremely high serum DHEAS level, at 7,546 ng/ml (reference < 4,000; ). A second blood sample confirmed the DHEAS excess, with even a higher serum level, at 8,835 ng/ml. In contrast, serum DHEA was in the normal range, at 443 ng/dl (reference < 750). Serum ACTH (4.8 pmol/L), cortisol (22.7 μg/dl), androstenedione (10 nmol/L), 17-OH progesterone (70 ng/dl), testosterone (28 ng/dl), luteinizing hormone (LH; 5.7 UI/L), follicle-stimulating hormone (FSH; 1.7 IU/L), as well as thyroid-stimulating hormone (TSH; 1.57 mIU/L), and free thyroxine (fT4; 14 pmol/L) levels were all within the normal range.\nThe serum steroid sulfatome was analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The high DHEAS serum level was confirmed. Interestingly, with the exception of cholesterol sulfate, several other sulfated steroids were found to be above the reference range, namely, pregnenolone sulfate, 17-hydroxypregnenolone sulfate, 16-α-hydroxy-DHEAS, androstenediol-3-sulfate, androsterone sulfate, and epiandrosterone sulfate (). In addition, the urinary steroid metabolome was delineated by gas chromatography-mass spectrometry (GC-MS) in a 24 h urinary sample. It revealed excessive excretion of DHEAS metabolites at 200% of the upper limit of the reference interval. Urinary analysis excluded any known enzyme defect of the adrenal steroid synthesis.\nFor exclusion of an autonomous hormone secretion by an adrenal or an ovarian tumor, administration of 0.5 mg dexamethasone four times daily on four consecutive days was performed which resulted in an efficient suppression of DHEAS and DHEA as well as their urinary metabolites. On day 5, the DHEAS level decreased to 1,199 ng/ml (13.6% of baseline; reference < 47.2%) and the DHEA level to 144 ng/dl (32% of baseline; reference < 38.9%) (). In addition, urinary cortisol metabolites were sufficiently suppressed during the dexamethasone test. Ultrasound and MRI scans of the adrenal glands and the ovaries were normal. No further deterioration in the patient's hormonal investigations was noted during the 4 year course of observation.\nFollowing the hypothesis that the high DHEAS level was likely to be hereditary, we sequenced the STS gene, which is responsible for the hydrolysis of aryl and alkyl steroid sulfates and catalyzes the conversion of DHEAS to DHEA (). Sequence analysis revealed a heterozygous single-base substitution (g.117217G>T) that results in a nonsense mutation at codon 173 (p.G173X). This mutation predicts a truncation of the carboxyl region of the STS enzyme that is implicated in substrate binding. The mutant allele contained two further variants within the fifth exon: a silent mutation (g.117309C>A) at codon 203 C → A (leucine), and a missense mutation at codon 464 G → T, which resulted in substitution of methionine for isoleucine (g.117465G>T). This nonsense mutation is not present in the Exome Variant Server. At 19 bp upstream in the genomic sequence of exon 10, we identified another C → T transition (g.207619C>T). The nonsense mutation p.G173X found in the patient was de novo as demonstrated by allele-specific amplification of the wild-type (wt) and mutant sequences (mut) of both parents' DNA samples. No partial gene deletion of the presumably intact allele outside exon 5 was detected by multiplex ligation-dependent probe amplification.\nBiological activity of STS was measured in the patient's blood leukocytes after addition of 1,2,6,7-3H-DHEAS. In our experimental setting, ~7 nmol DHEA was produced by 1 × 106 leukocytes per 4 h. The mean (SD) STS activity detected in patient's leukocytes was 107% in comparison to those of five healthy age-matched female controls. Therefore, normal hydrolytic activity of STS was revealed in the patient's blood leukocytes.\nNo clear explanation for the high levels of DHEAS connected to the STS gene structure and enzyme activity was found. Therefore, a defect of one or more transporter proteins was suggested (). On the one hand, a reduced steroid sulfate efflux activity in the liver would enhance serum levels; on the other hand, impaired steroid sulfate uptake from the circulation into peripheral target cells or hepatocytes would have the same effect. Prominent candidate efflux transporters were MRP2 and BCRP, both highly expressed at the canalicular membrane of hepatocytes and involved in the hepatobiliary elimination of many drugs and some endogenous substrates such as sulfated steroids (). However, as MRP2 deficiency would typically increase the levels of conjugated bilirubin in the plasma (Dubin–Johnson syndrome) () what was not seen in the patient, BCRP was the only candidate carrier for the efflux site. On the uptake site, several OATP and OAT carriers were on the list. However, as most of them show highly overlapping substrate specificities and redundant expression patterns (e.g., OATP1B1, OATP1B3, and OATP2B1 are expressed in the liver) (), it was supposed that a transport defect of one of these carriers could have been compensated by another member of the same carrier family. Therefore, we decided to select two carriers from the SLC10 carrier family, which are more unique in the sense of substrate specificity and tissue expression and which both show sodium-dependent transport of sulfated steroids (, ). In both carriers, genetic variants or mutations were described before with significantly reduced transport activity, associated with increased plasma levels of their substrates (–). However, as the determination of DHEAS serum levels is not included in standard diagnostics, elevated DHEAS levels may have been overseen in patients with such carrier defects. Using exon-spanning PCR, all exons of the abovementioned membrane transporters were sequenced. There were no relevant variants detected for the SLC10A1 and SLC10A6 genes. Sequence analysis revealed a heterozygous Q141K variant for BCRP. Interestingly, this variant has in its homozygous state previously been associated with reduced efflux transport activity ().

Patient 2. A 5-day-old male infant was admitted to our Neonatal Section because of jaundice for 3 days. Mild jaundice appeared at age 2 days. At the 5th day after birth, the total bilirubin increased to 310.1 μmol/L. Then the infant was referred to our clinic, where a laboratory test revealed elevated TBA as well as indirect hyperbilirubinemia (Table ), and thus the infant was admitted for further management. As the first child of a non-consanguineous couple, the patient was delivered vaginally at the gestational age of 37 weeks with the birth weight 3050 g. The parents were both healthy. Family history of any genetic disease was denied.\nOn physical examination, the body weight was 2910 g, with T 36.2°C, HR 130 beats/min, and RR 43 breaths/min. Jaundiced skin and sclera were observed. The lungs were clear on auscultation, and no abnormal heart sound or murmur was heard. There was no abdominal distention, and the liver and spleen were not palpable. Primitive reflexes were normal and no pathological reflexes could be found on nervous system examination.\nThe patient underwent phototherapy for 3 days. As a result, his jaundice subsided, and he was discharged at age 9 days. No special treatment was given thereafter, and the jaundice did not reappear. However, his serum TBA levels kept high in the following 1 month, and hence SLC10A1 analysis was performed at age 33 days to evaluate the possibility of NTCP deficiency. On Sanger sequencing of the UGT1A1 gene, no pathogenic variant was detected but three benign SNPs in the 3ʹ UTR, i.e. rs10929303, rs1042640 and rs8330 [].

Write a detailed clinical case vignette based on the following key phrases: Liver function abnormalities, Genetic disorders, Bile acid metabolism

Patient 1 was a 5–year-and-11-month-old female referred to the First Affiliated Hospital, Jinan University due to abnormal liver function discovered for 5 years and 7 months. When aged 4 months, she was admitted to a hospital in Guangzhou due to jaundice for 3 months, where physical examination revealed an enlarged liver 4.0 cm below the right costal margin, and a liver function test revealed elevated serum levels of total bilirubin (TBIL), direct bilirubin (DBIL), indirect bilirubin (IBIL), alanine transaminase (ALT), aspartate transaminase (AST), γ-glutamyl transpeptidase (GGT), and alkaline phosphatase (ALP), indicating cholestatic jaundice (). Blood amino acid spectrum analysis by tandem mass spectrometry (MS-MS) revealed raised citrulline, methionine, arginine, and threonine, while large quantities of galactose, galactitol, galactonate, and 4-hydroxyphenyllactate (4HPL) were detected on urinary gas chromatography-mass spectrometry (GC-MS) analysis. Considering the above clinical and laboratory findings, NICCD was suspected, and breast-feeding was stopped while a lactose-free and medium-chain triglycerides (MCT)-enriched formula was introduced. When aged 4.9 months, SLC25A13 genetic analysis in our hospital unveiled a homozygote of the c.852_855del4 mutation () and the diagnosis of NICCD was hence made. Thereafter, besides feeding with the therapeutic formula, supplemental foods rich in protein were encouraged. As a result, her liver function indices got improved gradually and returned to normal by age 10.2 months. However, the hypercholanemia was refractory, with total bile acid (TBA) levels fluctuating from 27.6 µmol/L to 340.2 µmol/L (reference range: 0–10 µmol/L) (). After the age 2 years, the patient showed a fondness for foods rich in protein and fat while an aversion to carbohydrate-rich diets.\nAs the first product of a non-consanguineous couple, the child was delivered spontaneously at the gestational age of 38 weeks and 3 days after an uneventful pregnancy, with a birth weight of 3.0 kg and body length 50 cm. The parents were healthy, and there was no family history of any genetic or infectious diseases.\nPhysical examination revealed a body temperature (T) 36.5°C, heart rate (HR) 115 beats/min (bpm), respiratory rate (RR) 20 bpm, weight (WT) 18 kg, height 107.0 cm. No jaundice was observed in the skin and sclera. The lungs were clear. No murmurs or abnormal heart sounds were heard. There was no abdominal distention, and the liver and spleen were not enlarged. Physiological reflexes were normal and no pathological reflexes could be found on nervous system examination. The extremities were warm, and the distal perfusion was excellent.\nLaboratory investigation showed otherwise normal biochemical indices but a TBA level of 48.7 µmol/L. In view of the intractable hypercholanemia, NTCP deficiency was highly suspected, and SLC10A1 genetic analysis was performed. As a result, the patient was a homozygote, while the parents, carriers, of the reportedly pathogenic variant c.800C > T(p.Ser267Phe)(). NTCP deficiency was thus definitely diagnosed. No specific therapy was given but close clinic follow-up was underway.

Patient 2. A 5-day-old male infant was admitted to our Neonatal Section because of jaundice for 3 days. Mild jaundice appeared at age 2 days. At the 5th day after birth, the total bilirubin increased to 310.1 μmol/L. Then the infant was referred to our clinic, where a laboratory test revealed elevated TBA as well as indirect hyperbilirubinemia (Table ), and thus the infant was admitted for further management. As the first child of a non-consanguineous couple, the patient was delivered vaginally at the gestational age of 37 weeks with the birth weight 3050 g. The parents were both healthy. Family history of any genetic disease was denied.\nOn physical examination, the body weight was 2910 g, with T 36.2°C, HR 130 beats/min, and RR 43 breaths/min. Jaundiced skin and sclera were observed. The lungs were clear on auscultation, and no abnormal heart sound or murmur was heard. There was no abdominal distention, and the liver and spleen were not palpable. Primitive reflexes were normal and no pathological reflexes could be found on nervous system examination.\nThe patient underwent phototherapy for 3 days. As a result, his jaundice subsided, and he was discharged at age 9 days. No special treatment was given thereafter, and the jaundice did not reappear. However, his serum TBA levels kept high in the following 1 month, and hence SLC10A1 analysis was performed at age 33 days to evaluate the possibility of NTCP deficiency. On Sanger sequencing of the UGT1A1 gene, no pathogenic variant was detected but three benign SNPs in the 3ʹ UTR, i.e. rs10929303, rs1042640 and rs8330 [].

Write a detailed clinical case vignette based on the following key phrases: Liver function abnormalities, Genetic disorders, Bile acid metabolism

An 18.5-year-old female was presented to the outpatient clinic due to overweight. Her height was 166.1 cm, her weight was 80.1 kg, and her body mass index (BMI) was 29.0 kg/m2. No clinical signs of hyperandrogenism or hypercortisolism were observed. The skin was normal; however, striae cutis distensae were seen. Neither hirsutism nor acanthosis nigricans was present. No indication of ichthyosis was noted. Pubertal development was complete, with breast stage B5, pubic hair stage PH5, menstrual periods were regular. Blood pressure was within the norm, at 125/80 mm Hg.\nThe patient fulfilled only two criteria for metabolic syndrome in adolescence by having disturbed glucose metabolism and abdominal obesity. Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) was increased to 6.9; oral glucose tolerance was pathological (2 h glucose concentration 165 mg/dl). Serum concentrations of high-density lipoprotein (HDL)-cholesterol (60 mg/dl) and triglycerides (108 mg/dl) were within the reference range, while cholesterol (232 mg/dl) and low-density lipoprotein (LDL)-cholesterol (186 mg/dl) were increased. The patient underwent a relatively successful lifestyle intervention, which enabled a stabilization of her BMI and a normalization of her oral glucose tolerance within 6 months.\nRoutine analysis of adrenal hormones revealed an extremely high serum DHEAS level, at 7,546 ng/ml (reference < 4,000; ). A second blood sample confirmed the DHEAS excess, with even a higher serum level, at 8,835 ng/ml. In contrast, serum DHEA was in the normal range, at 443 ng/dl (reference < 750). Serum ACTH (4.8 pmol/L), cortisol (22.7 μg/dl), androstenedione (10 nmol/L), 17-OH progesterone (70 ng/dl), testosterone (28 ng/dl), luteinizing hormone (LH; 5.7 UI/L), follicle-stimulating hormone (FSH; 1.7 IU/L), as well as thyroid-stimulating hormone (TSH; 1.57 mIU/L), and free thyroxine (fT4; 14 pmol/L) levels were all within the normal range.\nThe serum steroid sulfatome was analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The high DHEAS serum level was confirmed. Interestingly, with the exception of cholesterol sulfate, several other sulfated steroids were found to be above the reference range, namely, pregnenolone sulfate, 17-hydroxypregnenolone sulfate, 16-α-hydroxy-DHEAS, androstenediol-3-sulfate, androsterone sulfate, and epiandrosterone sulfate (). In addition, the urinary steroid metabolome was delineated by gas chromatography-mass spectrometry (GC-MS) in a 24 h urinary sample. It revealed excessive excretion of DHEAS metabolites at 200% of the upper limit of the reference interval. Urinary analysis excluded any known enzyme defect of the adrenal steroid synthesis.\nFor exclusion of an autonomous hormone secretion by an adrenal or an ovarian tumor, administration of 0.5 mg dexamethasone four times daily on four consecutive days was performed which resulted in an efficient suppression of DHEAS and DHEA as well as their urinary metabolites. On day 5, the DHEAS level decreased to 1,199 ng/ml (13.6% of baseline; reference < 47.2%) and the DHEA level to 144 ng/dl (32% of baseline; reference < 38.9%) (). In addition, urinary cortisol metabolites were sufficiently suppressed during the dexamethasone test. Ultrasound and MRI scans of the adrenal glands and the ovaries were normal. No further deterioration in the patient's hormonal investigations was noted during the 4 year course of observation.\nFollowing the hypothesis that the high DHEAS level was likely to be hereditary, we sequenced the STS gene, which is responsible for the hydrolysis of aryl and alkyl steroid sulfates and catalyzes the conversion of DHEAS to DHEA (). Sequence analysis revealed a heterozygous single-base substitution (g.117217G>T) that results in a nonsense mutation at codon 173 (p.G173X). This mutation predicts a truncation of the carboxyl region of the STS enzyme that is implicated in substrate binding. The mutant allele contained two further variants within the fifth exon: a silent mutation (g.117309C>A) at codon 203 C → A (leucine), and a missense mutation at codon 464 G → T, which resulted in substitution of methionine for isoleucine (g.117465G>T). This nonsense mutation is not present in the Exome Variant Server. At 19 bp upstream in the genomic sequence of exon 10, we identified another C → T transition (g.207619C>T). The nonsense mutation p.G173X found in the patient was de novo as demonstrated by allele-specific amplification of the wild-type (wt) and mutant sequences (mut) of both parents' DNA samples. No partial gene deletion of the presumably intact allele outside exon 5 was detected by multiplex ligation-dependent probe amplification.\nBiological activity of STS was measured in the patient's blood leukocytes after addition of 1,2,6,7-3H-DHEAS. In our experimental setting, ~7 nmol DHEA was produced by 1 × 106 leukocytes per 4 h. The mean (SD) STS activity detected in patient's leukocytes was 107% in comparison to those of five healthy age-matched female controls. Therefore, normal hydrolytic activity of STS was revealed in the patient's blood leukocytes.\nNo clear explanation for the high levels of DHEAS connected to the STS gene structure and enzyme activity was found. Therefore, a defect of one or more transporter proteins was suggested (). On the one hand, a reduced steroid sulfate efflux activity in the liver would enhance serum levels; on the other hand, impaired steroid sulfate uptake from the circulation into peripheral target cells or hepatocytes would have the same effect. Prominent candidate efflux transporters were MRP2 and BCRP, both highly expressed at the canalicular membrane of hepatocytes and involved in the hepatobiliary elimination of many drugs and some endogenous substrates such as sulfated steroids (). However, as MRP2 deficiency would typically increase the levels of conjugated bilirubin in the plasma (Dubin–Johnson syndrome) () what was not seen in the patient, BCRP was the only candidate carrier for the efflux site. On the uptake site, several OATP and OAT carriers were on the list. However, as most of them show highly overlapping substrate specificities and redundant expression patterns (e.g., OATP1B1, OATP1B3, and OATP2B1 are expressed in the liver) (), it was supposed that a transport defect of one of these carriers could have been compensated by another member of the same carrier family. Therefore, we decided to select two carriers from the SLC10 carrier family, which are more unique in the sense of substrate specificity and tissue expression and which both show sodium-dependent transport of sulfated steroids (, ). In both carriers, genetic variants or mutations were described before with significantly reduced transport activity, associated with increased plasma levels of their substrates (–). However, as the determination of DHEAS serum levels is not included in standard diagnostics, elevated DHEAS levels may have been overseen in patients with such carrier defects. Using exon-spanning PCR, all exons of the abovementioned membrane transporters were sequenced. There were no relevant variants detected for the SLC10A1 and SLC10A6 genes. Sequence analysis revealed a heterozygous Q141K variant for BCRP. Interestingly, this variant has in its homozygous state previously been associated with reduced efflux transport activity ().

Patient 2 was a 1-year-and-1-month-old male visiting our clinic due to hypercholanemia discovered for 11 months. At the age 2 months, he was referred to a local hospital because of prolonged jaundice for about 1 month. On biochemistry analysis, elevated serum levels of AST, GGT, ALP, TBIL, DBIL, and IBIL, together with decreased level of albumin were detected, and notably, the TBA level reached 268.7 µmol/L (). Subsequent urinary GC-MS analysis detected elevated 4-hydroxyphenylpyruvate (4-HPPV) and 4HPL, while raised levels of citrulline, methionine, and threonine were detected on MS-MS analysis of blood sample. When aged 2.1 months, the infant undertook SLC25A13 analysis in our hospital, and proved to be a homozygote of the c.852_855del4 mutation (), and the diagnosis of NICCD was thus made. Then breast-feeding was stopped and a lactose-free and MCT-enriched formula was given. Then his jaundice disappeared rapidly, and serum bilirubin levels returned to normal at his age 5.5 months (). However, the hypercholanemia persisted, even beyond 1 year of age (). No steatorrhea or acholic stool was observed during the course of the disease.\nAs the first child of a non-consanguineous couple, the patient was delivered vaginally at the gestational age of 37 weeks and 4 days with the birth weight 2700 g. The Apgar score was 9 points at 1 min and 10 points at 5 min after umbilical ligation. Parents were both hepatitis B virus (HBV) carriers, who were apparently healthy but with slightly raised serum TBA levels (). Family history of any genetic diseases was denied.\nPhysical examination revealed a body T 36.6°C, weight 10.5 kg, HR 126 bpm, and RR 32 bpm. No jaundiced skin and sclera was observed. On auscultation, no abnormal sounds were heard on the lungs and heart. There was no abdominal distention, and the liver and spleen were non-palpable. Primitive reflexes were normal and pathological reflexes could not be found on nervous system examination.\nLaboratory test at visiting revealed a serum TBA level of 234.5 µmol/L and otherwise normal indices. SLC10A1 genetic analysis demonstrated that the patient was a homozygote, and his parents, carriers, of the variant c.800C > T (p.Ser267Phe) (). The diagnosis of NTCP deficiency was thus made. No specific therapy was given but clinic follow up was suggested. His serum TBA level was 148 µmol/L () when aged 1 year and 6 months, and a fondness for low-carbohydrate and high-protein foods was noticed since the age of 1 year.

Write a detailed clinical case vignette based on the following key phrases: Liver function abnormalities, Genetic disorders, Bile acid metabolism

Patient 2 was a 1-year-and-1-month-old male visiting our clinic due to hypercholanemia discovered for 11 months. At the age 2 months, he was referred to a local hospital because of prolonged jaundice for about 1 month. On biochemistry analysis, elevated serum levels of AST, GGT, ALP, TBIL, DBIL, and IBIL, together with decreased level of albumin were detected, and notably, the TBA level reached 268.7 µmol/L (). Subsequent urinary GC-MS analysis detected elevated 4-hydroxyphenylpyruvate (4-HPPV) and 4HPL, while raised levels of citrulline, methionine, and threonine were detected on MS-MS analysis of blood sample. When aged 2.1 months, the infant undertook SLC25A13 analysis in our hospital, and proved to be a homozygote of the c.852_855del4 mutation (), and the diagnosis of NICCD was thus made. Then breast-feeding was stopped and a lactose-free and MCT-enriched formula was given. Then his jaundice disappeared rapidly, and serum bilirubin levels returned to normal at his age 5.5 months (). However, the hypercholanemia persisted, even beyond 1 year of age (). No steatorrhea or acholic stool was observed during the course of the disease.\nAs the first child of a non-consanguineous couple, the patient was delivered vaginally at the gestational age of 37 weeks and 4 days with the birth weight 2700 g. The Apgar score was 9 points at 1 min and 10 points at 5 min after umbilical ligation. Parents were both hepatitis B virus (HBV) carriers, who were apparently healthy but with slightly raised serum TBA levels (). Family history of any genetic diseases was denied.\nPhysical examination revealed a body T 36.6°C, weight 10.5 kg, HR 126 bpm, and RR 32 bpm. No jaundiced skin and sclera was observed. On auscultation, no abnormal sounds were heard on the lungs and heart. There was no abdominal distention, and the liver and spleen were non-palpable. Primitive reflexes were normal and pathological reflexes could not be found on nervous system examination.\nLaboratory test at visiting revealed a serum TBA level of 234.5 µmol/L and otherwise normal indices. SLC10A1 genetic analysis demonstrated that the patient was a homozygote, and his parents, carriers, of the variant c.800C > T (p.Ser267Phe) (). The diagnosis of NTCP deficiency was thus made. No specific therapy was given but clinic follow up was suggested. His serum TBA level was 148 µmol/L () when aged 1 year and 6 months, and a fondness for low-carbohydrate and high-protein foods was noticed since the age of 1 year.

Patient 1 was a 5–year-and-11-month-old female referred to the First Affiliated Hospital, Jinan University due to abnormal liver function discovered for 5 years and 7 months. When aged 4 months, she was admitted to a hospital in Guangzhou due to jaundice for 3 months, where physical examination revealed an enlarged liver 4.0 cm below the right costal margin, and a liver function test revealed elevated serum levels of total bilirubin (TBIL), direct bilirubin (DBIL), indirect bilirubin (IBIL), alanine transaminase (ALT), aspartate transaminase (AST), γ-glutamyl transpeptidase (GGT), and alkaline phosphatase (ALP), indicating cholestatic jaundice (). Blood amino acid spectrum analysis by tandem mass spectrometry (MS-MS) revealed raised citrulline, methionine, arginine, and threonine, while large quantities of galactose, galactitol, galactonate, and 4-hydroxyphenyllactate (4HPL) were detected on urinary gas chromatography-mass spectrometry (GC-MS) analysis. Considering the above clinical and laboratory findings, NICCD was suspected, and breast-feeding was stopped while a lactose-free and medium-chain triglycerides (MCT)-enriched formula was introduced. When aged 4.9 months, SLC25A13 genetic analysis in our hospital unveiled a homozygote of the c.852_855del4 mutation () and the diagnosis of NICCD was hence made. Thereafter, besides feeding with the therapeutic formula, supplemental foods rich in protein were encouraged. As a result, her liver function indices got improved gradually and returned to normal by age 10.2 months. However, the hypercholanemia was refractory, with total bile acid (TBA) levels fluctuating from 27.6 µmol/L to 340.2 µmol/L (reference range: 0–10 µmol/L) (). After the age 2 years, the patient showed a fondness for foods rich in protein and fat while an aversion to carbohydrate-rich diets.\nAs the first product of a non-consanguineous couple, the child was delivered spontaneously at the gestational age of 38 weeks and 3 days after an uneventful pregnancy, with a birth weight of 3.0 kg and body length 50 cm. The parents were healthy, and there was no family history of any genetic or infectious diseases.\nPhysical examination revealed a body temperature (T) 36.5°C, heart rate (HR) 115 beats/min (bpm), respiratory rate (RR) 20 bpm, weight (WT) 18 kg, height 107.0 cm. No jaundice was observed in the skin and sclera. The lungs were clear. No murmurs or abnormal heart sounds were heard. There was no abdominal distention, and the liver and spleen were not enlarged. Physiological reflexes were normal and no pathological reflexes could be found on nervous system examination. The extremities were warm, and the distal perfusion was excellent.\nLaboratory investigation showed otherwise normal biochemical indices but a TBA level of 48.7 µmol/L. In view of the intractable hypercholanemia, NTCP deficiency was highly suspected, and SLC10A1 genetic analysis was performed. As a result, the patient was a homozygote, while the parents, carriers, of the reportedly pathogenic variant c.800C > T(p.Ser267Phe)(). NTCP deficiency was thus definitely diagnosed. No specific therapy was given but close clinic follow-up was underway.

Write a detailed clinical case vignette based on the following key phrases: Liver function abnormalities, Genetic disorders, Bile acid metabolism

An 18.5-year-old female was presented to the outpatient clinic due to overweight. Her height was 166.1 cm, her weight was 80.1 kg, and her body mass index (BMI) was 29.0 kg/m2. No clinical signs of hyperandrogenism or hypercortisolism were observed. The skin was normal; however, striae cutis distensae were seen. Neither hirsutism nor acanthosis nigricans was present. No indication of ichthyosis was noted. Pubertal development was complete, with breast stage B5, pubic hair stage PH5, menstrual periods were regular. Blood pressure was within the norm, at 125/80 mm Hg.\nThe patient fulfilled only two criteria for metabolic syndrome in adolescence by having disturbed glucose metabolism and abdominal obesity. Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) was increased to 6.9; oral glucose tolerance was pathological (2 h glucose concentration 165 mg/dl). Serum concentrations of high-density lipoprotein (HDL)-cholesterol (60 mg/dl) and triglycerides (108 mg/dl) were within the reference range, while cholesterol (232 mg/dl) and low-density lipoprotein (LDL)-cholesterol (186 mg/dl) were increased. The patient underwent a relatively successful lifestyle intervention, which enabled a stabilization of her BMI and a normalization of her oral glucose tolerance within 6 months.\nRoutine analysis of adrenal hormones revealed an extremely high serum DHEAS level, at 7,546 ng/ml (reference < 4,000; ). A second blood sample confirmed the DHEAS excess, with even a higher serum level, at 8,835 ng/ml. In contrast, serum DHEA was in the normal range, at 443 ng/dl (reference < 750). Serum ACTH (4.8 pmol/L), cortisol (22.7 μg/dl), androstenedione (10 nmol/L), 17-OH progesterone (70 ng/dl), testosterone (28 ng/dl), luteinizing hormone (LH; 5.7 UI/L), follicle-stimulating hormone (FSH; 1.7 IU/L), as well as thyroid-stimulating hormone (TSH; 1.57 mIU/L), and free thyroxine (fT4; 14 pmol/L) levels were all within the normal range.\nThe serum steroid sulfatome was analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The high DHEAS serum level was confirmed. Interestingly, with the exception of cholesterol sulfate, several other sulfated steroids were found to be above the reference range, namely, pregnenolone sulfate, 17-hydroxypregnenolone sulfate, 16-α-hydroxy-DHEAS, androstenediol-3-sulfate, androsterone sulfate, and epiandrosterone sulfate (). In addition, the urinary steroid metabolome was delineated by gas chromatography-mass spectrometry (GC-MS) in a 24 h urinary sample. It revealed excessive excretion of DHEAS metabolites at 200% of the upper limit of the reference interval. Urinary analysis excluded any known enzyme defect of the adrenal steroid synthesis.\nFor exclusion of an autonomous hormone secretion by an adrenal or an ovarian tumor, administration of 0.5 mg dexamethasone four times daily on four consecutive days was performed which resulted in an efficient suppression of DHEAS and DHEA as well as their urinary metabolites. On day 5, the DHEAS level decreased to 1,199 ng/ml (13.6% of baseline; reference < 47.2%) and the DHEA level to 144 ng/dl (32% of baseline; reference < 38.9%) (). In addition, urinary cortisol metabolites were sufficiently suppressed during the dexamethasone test. Ultrasound and MRI scans of the adrenal glands and the ovaries were normal. No further deterioration in the patient's hormonal investigations was noted during the 4 year course of observation.\nFollowing the hypothesis that the high DHEAS level was likely to be hereditary, we sequenced the STS gene, which is responsible for the hydrolysis of aryl and alkyl steroid sulfates and catalyzes the conversion of DHEAS to DHEA (). Sequence analysis revealed a heterozygous single-base substitution (g.117217G>T) that results in a nonsense mutation at codon 173 (p.G173X). This mutation predicts a truncation of the carboxyl region of the STS enzyme that is implicated in substrate binding. The mutant allele contained two further variants within the fifth exon: a silent mutation (g.117309C>A) at codon 203 C → A (leucine), and a missense mutation at codon 464 G → T, which resulted in substitution of methionine for isoleucine (g.117465G>T). This nonsense mutation is not present in the Exome Variant Server. At 19 bp upstream in the genomic sequence of exon 10, we identified another C → T transition (g.207619C>T). The nonsense mutation p.G173X found in the patient was de novo as demonstrated by allele-specific amplification of the wild-type (wt) and mutant sequences (mut) of both parents' DNA samples. No partial gene deletion of the presumably intact allele outside exon 5 was detected by multiplex ligation-dependent probe amplification.\nBiological activity of STS was measured in the patient's blood leukocytes after addition of 1,2,6,7-3H-DHEAS. In our experimental setting, ~7 nmol DHEA was produced by 1 × 106 leukocytes per 4 h. The mean (SD) STS activity detected in patient's leukocytes was 107% in comparison to those of five healthy age-matched female controls. Therefore, normal hydrolytic activity of STS was revealed in the patient's blood leukocytes.\nNo clear explanation for the high levels of DHEAS connected to the STS gene structure and enzyme activity was found. Therefore, a defect of one or more transporter proteins was suggested (). On the one hand, a reduced steroid sulfate efflux activity in the liver would enhance serum levels; on the other hand, impaired steroid sulfate uptake from the circulation into peripheral target cells or hepatocytes would have the same effect. Prominent candidate efflux transporters were MRP2 and BCRP, both highly expressed at the canalicular membrane of hepatocytes and involved in the hepatobiliary elimination of many drugs and some endogenous substrates such as sulfated steroids (). However, as MRP2 deficiency would typically increase the levels of conjugated bilirubin in the plasma (Dubin–Johnson syndrome) () what was not seen in the patient, BCRP was the only candidate carrier for the efflux site. On the uptake site, several OATP and OAT carriers were on the list. However, as most of them show highly overlapping substrate specificities and redundant expression patterns (e.g., OATP1B1, OATP1B3, and OATP2B1 are expressed in the liver) (), it was supposed that a transport defect of one of these carriers could have been compensated by another member of the same carrier family. Therefore, we decided to select two carriers from the SLC10 carrier family, which are more unique in the sense of substrate specificity and tissue expression and which both show sodium-dependent transport of sulfated steroids (, ). In both carriers, genetic variants or mutations were described before with significantly reduced transport activity, associated with increased plasma levels of their substrates (–). However, as the determination of DHEAS serum levels is not included in standard diagnostics, elevated DHEAS levels may have been overseen in patients with such carrier defects. Using exon-spanning PCR, all exons of the abovementioned membrane transporters were sequenced. There were no relevant variants detected for the SLC10A1 and SLC10A6 genes. Sequence analysis revealed a heterozygous Q141K variant for BCRP. Interestingly, this variant has in its homozygous state previously been associated with reduced efflux transport activity ().

Patient 1 was a 5–year-and-11-month-old female referred to the First Affiliated Hospital, Jinan University due to abnormal liver function discovered for 5 years and 7 months. When aged 4 months, she was admitted to a hospital in Guangzhou due to jaundice for 3 months, where physical examination revealed an enlarged liver 4.0 cm below the right costal margin, and a liver function test revealed elevated serum levels of total bilirubin (TBIL), direct bilirubin (DBIL), indirect bilirubin (IBIL), alanine transaminase (ALT), aspartate transaminase (AST), γ-glutamyl transpeptidase (GGT), and alkaline phosphatase (ALP), indicating cholestatic jaundice (). Blood amino acid spectrum analysis by tandem mass spectrometry (MS-MS) revealed raised citrulline, methionine, arginine, and threonine, while large quantities of galactose, galactitol, galactonate, and 4-hydroxyphenyllactate (4HPL) were detected on urinary gas chromatography-mass spectrometry (GC-MS) analysis. Considering the above clinical and laboratory findings, NICCD was suspected, and breast-feeding was stopped while a lactose-free and medium-chain triglycerides (MCT)-enriched formula was introduced. When aged 4.9 months, SLC25A13 genetic analysis in our hospital unveiled a homozygote of the c.852_855del4 mutation () and the diagnosis of NICCD was hence made. Thereafter, besides feeding with the therapeutic formula, supplemental foods rich in protein were encouraged. As a result, her liver function indices got improved gradually and returned to normal by age 10.2 months. However, the hypercholanemia was refractory, with total bile acid (TBA) levels fluctuating from 27.6 µmol/L to 340.2 µmol/L (reference range: 0–10 µmol/L) (). After the age 2 years, the patient showed a fondness for foods rich in protein and fat while an aversion to carbohydrate-rich diets.\nAs the first product of a non-consanguineous couple, the child was delivered spontaneously at the gestational age of 38 weeks and 3 days after an uneventful pregnancy, with a birth weight of 3.0 kg and body length 50 cm. The parents were healthy, and there was no family history of any genetic or infectious diseases.\nPhysical examination revealed a body temperature (T) 36.5°C, heart rate (HR) 115 beats/min (bpm), respiratory rate (RR) 20 bpm, weight (WT) 18 kg, height 107.0 cm. No jaundice was observed in the skin and sclera. The lungs were clear. No murmurs or abnormal heart sounds were heard. There was no abdominal distention, and the liver and spleen were not enlarged. Physiological reflexes were normal and no pathological reflexes could be found on nervous system examination. The extremities were warm, and the distal perfusion was excellent.\nLaboratory investigation showed otherwise normal biochemical indices but a TBA level of 48.7 µmol/L. In view of the intractable hypercholanemia, NTCP deficiency was highly suspected, and SLC10A1 genetic analysis was performed. As a result, the patient was a homozygote, while the parents, carriers, of the reportedly pathogenic variant c.800C > T(p.Ser267Phe)(). NTCP deficiency was thus definitely diagnosed. No specific therapy was given but close clinic follow-up was underway.

Write a detailed clinical case vignette based on the following key phrases: Liver function abnormalities, Genetic disorders, Bile acid metabolism

A 45-year-old man was admitted for a progressively worsening headache over 2 weeks. He denied history of recent head trauma or anticoagulation and antiplatelet medication. General and neurologic examinations were not remarkable on admission. Routine laboratory investigations including coagulation profiles and platelet function were within normal limits. Head computed tomography (CT) on admission revealed an isodense CSDH on the right hemisphere with mild midline shift (Fig. a). A CT angiography (CTA) was performed to rule out any intracranial vascular malformation. A DAVF was noticed at the transverse sinus with dilated cortical venous drainage (Fig. b). So, a digital subtraction angiography (DSA) of the external carotid artery and DAVF embolization was planned.\nNo anomaly was noticed during selective angiography of the internal carotid and vertebral arteries and the left external carotid artery. Selective angiography of the right external carotid artery showed that the DAVF was located at the transverse sinus and fed by posterior branch of the middle meningeal artery (MMA), the occipital artery, and the posterior meningeal artery and drained to the occipital cortical veins with venous ectasia (Fig. a-b). The DAVF was classified as type IV according to the Cognard classification. The embolization was performed via the MMA. The Headway duo catheter was used and accessed to the DAVF, and Onyx was injected until the shunt disappeared (Fig. c-d). The patient experienced an uneventful recovery. His CSDH gradually resolved in 1 month (Fig. ). No neurologic deficit was noticed.\nA PubMed search of published studies written in English and Chinese was conducted on June 30th, 2017. The following key words were used in relevant combinations: dural arteriovenous fistula, dural arteriovenous malformation, subdural hematoma, subdural haematoma, subdural hemorrhage, and subdural haemorrhage. The reference lists of the identified articles were also manually searched for additional studies. Studies of which full text could not be obtained or those without sufficient individualized description of the isolated SDH cases mixed in larger case series were excluded.\nFinally, 13 articles containing 14 patients were identified [–]. In all 15 patients (9 females, 60%) including 1 case in our institution were included for the final interpretation (Table ). The inflicted patients were aged from 27 to 82 years (55.5 ± 8.6).Of note, 12 (80%) of the 15 patients were aged between 40 and 60 years of age, and 8 (53.3%) patients were between 50 and 60 years. Sides of the DAVF or SDH were obtained in 13 patients with 9 (69.2%) located at the left side and 4 at the right side. The intracranial locations of DAVF were anterior fossa (2), middle fossa (2), frontal region (2), parietal region (3), temporal region (2), and occipital region (2). The types of SDH were CSDH (7/15), acute SDH (ASDH) (7/15), and undefined SDH (1/15). Of the 12 patients feeding artery could be identified, MMA was the commonest feeding artery (8/12, 66.7%). Multiple feeding arteries were identified in 3 (25%) patients. The causes of DAVF were only defined in 3 patients (2 iatrogenic and 1 traumatic), with the rest undefined or not mentioned. Cognard classifications (Table ) of the DAVF were reported or deduced from the reports in 12 patients, with type I, type III, and type IV in 7, 2, and 3 patients respectively. The treatment strategies included hematoma evacuation (2/15), CSDH drainage and DAVF embolization (5/15), craniotomy and DAVF resection (3/15), DAVF embolization and hematoma evacuation (1/15), DAVF embolization (2/15), and not applicable or not mentioned (2/15). Of the 12 patients with direct description of outcome, 7 (58.3%) patients were neurological intact, 3 (25%) patients with neurological deficits, and 2 (16.7%) died.

A 38-year-old woman on oral contraceptives presented with headache and difficulty speaking. She had no other significant past medical history. A left frontal SDH and left temporal venous infarct with a left transverse sinus thrombosis was demonstrated on CT and MRI []. A hypercoagulable work-up did not reveal any additional thrombophilias. She was initially managed with systemic anticoagulation using intravenous heparin. After serial neurologic examinations and repeat CT, head imaging demonstrated no further bleeding; she was transitioned to oral warfarin and discharged home. She had excellent neurologic recovery (modified Rankin score 0) at 3 months follow up visit.

Write a detailed clinical case vignette based on the following key phrases: Subdural Hematoma, Cerebral Venous Thrombosis, Dural Arteriovenous Fistula

A 38-year-old woman on oral contraceptives presented with headache and difficulty speaking. She had no other significant past medical history. A left frontal SDH and left temporal venous infarct with a left transverse sinus thrombosis was demonstrated on CT and MRI []. A hypercoagulable work-up did not reveal any additional thrombophilias. She was initially managed with systemic anticoagulation using intravenous heparin. After serial neurologic examinations and repeat CT, head imaging demonstrated no further bleeding; she was transitioned to oral warfarin and discharged home. She had excellent neurologic recovery (modified Rankin score 0) at 3 months follow up visit.

We report a case of a 23-year-old male, known case of Down’s syndrome, who presented to our Emergency Department with a complaint of severe headache for three days. It was accompanied by nausea, vomiting, and confusion. There was no history of trauma, seizures, loss of consciousness, change in vision, or relevant signs of virus infection. He was not on any regular medications. His medical background included surgical closure of ventricular septal defects in his childhood. There was no past medical or family history of coagulopathies.\nOn examination, his Glasgow coma score was 14, with normal vital signs. On neurological examination, the patient was confused, with dense right-sided hemiparesis. Liver function test, prothrombin time, partial thromboplastin time, and international normalized ratio were all within normal range. The brain CT scan revealed left-sided subacute SDH with a 12 mm midline shift and uncal herniation ().\nThe patient underwent emergent left-sided craniotomy and SDH evacuation. The blood evacuated was a mixture of dark stained blood and clots. Post-surgery, the patient’s consciousness level returned to normal, and he regained full power in all limbs. His post-operative CT scan showed optimal evacuation of the left-sided hematoma. There was also a new finding of a small right-sided SDH in the parietal region with no significant mass effect (). The CT scans review showed hyperdense areas in the transverse and sigmoid sinus; this raised suspicion of thrombosis. Magnetic resonance venography (MRV) confirmed the diagnosis of CVST in the right transverse and sigmoid sinuses with loss of flow signal ().\nClinically, the patient made an excellent post-operative recovery. After the diagnosis of CVST, we obtained neurology opinion and considered it risky to commence therapeutic anticoagulation in the early post-operative phase. He was started on a prophylactic dose of low molecular heparin. The patient was discharged home one week after surgery. Subsequently, he was readmitted electively two weeks later and was commenced on Apixaban. He was followed up regularly in outpatients and was asymptomatic.\nThe patient re-presented three months later complaining of a headache and recurrent vomiting, with normal consciousness levels. His repeat brain CT showed recollection of hematoma in the left subdural space (). An updated MRV revealed an interval shrinkage of the thrombus in the right sigmoid venous sinus; however, the reduced flow was seen through the sinus. The medical decision was to stop the anticoagulation, and the patient underwent reopening of the left-sided craniotomy and evacuation of the recurrent SDH. He recovered well after surgery, and we elected not to restart anticoagulation and follow-him clinically.\nThe patient remains clinically well. Interval MRI and MRV scans at six months show complete resolution of the SDH, with residual partial thrombosis of the right sigmoid sinus; however, the sinus is patent, and the venous flow is restored ().

Write a detailed clinical case vignette based on the following key phrases: Subdural Hematoma, Cerebral Venous Thrombosis, Dural Arteriovenous Fistula

A 38-year-old woman on oral contraceptives presented with headache and difficulty speaking. She had no other significant past medical history. A left frontal SDH and left temporal venous infarct with a left transverse sinus thrombosis was demonstrated on CT and MRI []. A hypercoagulable work-up did not reveal any additional thrombophilias. She was initially managed with systemic anticoagulation using intravenous heparin. After serial neurologic examinations and repeat CT, head imaging demonstrated no further bleeding; she was transitioned to oral warfarin and discharged home. She had excellent neurologic recovery (modified Rankin score 0) at 3 months follow up visit.

A 40-year-old female presented to an emergency in altered sensorium with right hemiplegia with a history of a severe headache and multiple episodes of vomiting 1 day prior to admission. She was on oral contraceptives for last 2 years. Her Glasgow Coma Scale at admission was E1M3V1 and left pupil was dilated and not reacting to light. Computed tomography (CT) of head revealed venous infarct in left temporo-occipito-parietal region with linear area of hemorrhage within it with large left fronto-temporo-parietal acute subdural hematoma with midline shift of 9 mm toward right side with subfalcine herniation with descending transtentorial herniation with sub-arachnoid hemorrhage in the left parietal and occipital sulci with diffuse cerebral edema [].\nCT venography revealed thrombosis in superior sagittal sinus extending to adjacent cortical veins []. She was immediately taken for surgery, and a left fronto-temporo-parietal decompressive craniectomy was performed with the evacuation of acute subdural hematoma and lax duroplasty. However, she continued to deteriorate in the postoperative period and died on the first postoperative day.

Write a detailed clinical case vignette based on the following key phrases: Subdural Hematoma, Cerebral Venous Thrombosis, Dural Arteriovenous Fistula

A 25-year-old primigravida with a history of pre-eclampsia was brought to the emergency department with sudden onset of severe headache. The headache started two days after delivery. It was followed by confusion and loss of consciousness over a few hours. On initial evaluation, the patient was confused with a Glasgow Coma Scale (GCS) of 12/15, blood pressure of 130/90 mmHg, pulse rate of 82 beats/min, respiratory rate of 30/min, temperature 98°C, and oxygen saturation of 97 mmHg at room temperature. On physical examination, bilateral equivocal planters were noted with no other significant findings, and bilateral papillary edema on fundoscopy was seen. The rest of the review system was unremarkable. She underwent an urgent MRI with magnetic resonance venography (MRV) of the brain, which showed right transverse sinus thrombosis with an element of SAH (Figure ).\nCoagulation profile, including thrombin time (TT), prothrombin time (PT), partial thromboplastin time (PTT), antithrombin III, fibrinogen, proteins C and S, antiphospholipid antibody titers, and homocysteine levels, were normal. She was started on a half dosage of low molecular weight heparin (LMWH) (60 mg subcutaneously once a day) with regular monitoring of her blood pressure and GCS. Her GCS started improving; therefore, she was continued on a half dose of LMWH for 10 days, and brain MRI was repeated after 10 days, which showed the gradual resolution of SAH (Figure ). The quantity of LMWH was doubled, and warfarin was started after a full dose of LMWH. After improving her GCS and achievement of international normalized ratio (INR) of two to three, she was discharged with the advice of regular INR monitoring and follow-up to the outpatient department. On follow-up at six weeks, MRI with MRV was repeated, which showed thrombosis had resolved, although a mild filling defect was noted. She was kept on anticoagulants for one year, and on further follow-up at six months, she was doing well.

A 38-year-old woman on oral contraceptives presented with headache and difficulty speaking. She had no other significant past medical history. A left frontal SDH and left temporal venous infarct with a left transverse sinus thrombosis was demonstrated on CT and MRI []. A hypercoagulable work-up did not reveal any additional thrombophilias. She was initially managed with systemic anticoagulation using intravenous heparin. After serial neurologic examinations and repeat CT, head imaging demonstrated no further bleeding; she was transitioned to oral warfarin and discharged home. She had excellent neurologic recovery (modified Rankin score 0) at 3 months follow up visit.

Write a detailed clinical case vignette based on the following key phrases: Subdural Hematoma, Cerebral Venous Thrombosis, Dural Arteriovenous Fistula

A 38-year-old woman on oral contraceptives presented with headache and difficulty speaking. She had no other significant past medical history. A left frontal SDH and left temporal venous infarct with a left transverse sinus thrombosis was demonstrated on CT and MRI []. A hypercoagulable work-up did not reveal any additional thrombophilias. She was initially managed with systemic anticoagulation using intravenous heparin. After serial neurologic examinations and repeat CT, head imaging demonstrated no further bleeding; she was transitioned to oral warfarin and discharged home. She had excellent neurologic recovery (modified Rankin score 0) at 3 months follow up visit.

This 67-year-old male man has had a progressively worsening pain on the left cranium over 2 weeks that intractable to some analgesics. There was no recent head trauma or other medical disease in his history. On admission, the general physical and neurologic investigations were not remarkable. Routine laboratory evaluations including coagulation profiles and platelet function were within normal limits.\nBrain computed tomography (CT) scans revealed an isodense left-sided CSDH with marked cerebral shifting (). There was no evidence of source of this hemorrhage with temporal predilection on the CT angiogram. On magnetic resonance (MR) image subsequently obtained, the abnormal intensity within the subarachnoid space and the brain parenchyma was not visible. The patency without steno-occlusion in both transverse and sigmoid sinuses was clearly delineated on T2-weighted sequences (). This patient has received a trephination and SDH drainage, after that he was sent home with resolution of headache. Approximately 2 weeks later, however, he developed an excruciating pain in the temporal and parietal regions with recurrence of subdural collection. The site and density of hematoma was similar to the first presentation (). He was immediately returned for subdural irrigation and decompression through the prior burr-holes. The patient's clinical course was not eventful, but he complained of a mild headache again. Follow-up CT scanned just prior to discharge was strikingly for the newly-formed thin hematoma at the operative site (). Another evacuation of this subacute subdural clot was not deemed to be necessary.\nAt this time, an active intervention was sought for this patient who had an intractably recurring CSDH. On the 7th day after the second surgery, angiography was performed to rule out an occult vascular lesion. A flow-guided type microcatheter (Prowler 10™, Cordis Neurovascular, Miami Lakes, FL, USA) was positioned in the main trunk of the MMA for selective angiography. The frontal and parietal branch of the MMA was appeared normally, and the abnormal membrane staining on the affected side was not detected. A left external carotid angiogram disclosed a dural AVF between the petrosquamosal branch of the MMA and the transverse-sigmoid sinus without retrograde cortical venous draining. The AV shunt had no connection to the internal carotid artery and its branches. It was suggested that the bleeding from the draining venous system of the dural AVF led to refractory CSDH. The microcatheter was introduced into the petrosquamosal branch of the MMA, thereafter polyvinyl alcohol particles ranging 150 to 250 µm were distally injected (). After trans-arterial obliteration of the feeder and fistula, the AV shunt disappeared. The recurrent hematoma of this patient did not increase, and his complaints of headache gradually subsided. The brain CT at one year following the embolization therapy revealed complete regression of the subdural hematomas ().

Write a detailed clinical case vignette based on the following key phrases: Subdural Hematoma, Cerebral Venous Thrombosis, Dural Arteriovenous Fistula

A 66-year-old male with a recent syncope-related fall and closed head injury presented with progressively worsening gait instability, dizziness, and headaches. The fall occurred 1 week before presentation. On examination, no focal neurologic deficits were found. Noncontrast head CT demonstrated a 7 mm right convexity mixed density subdural hematoma [ and ]. Given his significant headaches and progressive functional decline, MMA embolization was performed as primary treatment. Intraprocedural digital subtraction angiogram revealed a right parietal Cognard Grade I DAVF [ and ]. Given the absence of cortical venous reflux and benign natural history of the fistula, the remainder of the procedure did not deviate from routine MMA embolization. The right temporal and right frontoparietal branches of the MMA were embolized with n-BCA glue with indirect penetration of liquid embolic into the fistulous point. Following embolization, there was no further opacification of the fistula. The patient experienced no procedure-related complication and was discharged the subsequent day. At 1-month follow-up, there was complete resolution of his presenting symptoms and surveillance CT demonstrated no residual SDH.

A 38-year-old woman on oral contraceptives presented with headache and difficulty speaking. She had no other significant past medical history. A left frontal SDH and left temporal venous infarct with a left transverse sinus thrombosis was demonstrated on CT and MRI []. A hypercoagulable work-up did not reveal any additional thrombophilias. She was initially managed with systemic anticoagulation using intravenous heparin. After serial neurologic examinations and repeat CT, head imaging demonstrated no further bleeding; she was transitioned to oral warfarin and discharged home. She had excellent neurologic recovery (modified Rankin score 0) at 3 months follow up visit.

Write a detailed clinical case vignette based on the following key phrases: Subdural Hematoma, Cerebral Venous Thrombosis, Dural Arteriovenous Fistula

A 58-year-old right-handed postmenopausal woman presented to the emergency with progressively increasing holocephalic headache for 3 days. She did not have fever, nausea, and vomiting. The headache gradually worsened in severity and on the day of presentation, she developed a generalized tonic clonic seizure. Apart from the history of well-controlled diabetes mellitus, she did not have significant past medical, personal, and family history. She had not received any vaccines in the recent past. On examination, she was ill-looking, but her vital signs were stable. She had Wernicke's aphasia. She did not have disc edema; cranial nerve examination was normal, and she did not have any focal deficits.\nAn urgent CT scan of the head without contrast showed left temporal hematoma with surrounding vasogenic edema (Figure ). Hemorrhagic picture was noted in the insular cistern (Figure ), left fronto-temporal subdural space (Figure ), the perimesencephalic, ambient and suprasellar cisterns (Figures and ), and the sulci of the left temporo-parietal lobes (Figures and ). There was a subtle dense clot sign in the left transverse sinus (Figure ). She was diagnosed as having left transverse sinus thrombosis leading to left temporal hematoma, SAH and SDH. She was treated with low molecular weight heparin, levetiracetam, and 3% hypertonic saline. The magnetic resonance venography (MRV) done the following day confirmed the presence of left transverse sinus thrombosis (Figure ). CT angiography of the brain did not reveal any vascular malformations. Her complete blood counts, coagulation profiles, routine blood chemistry, and C-reactive protein were within normal limits. Antinuclear antibody and SARS-CoV-2 RNA polymerase chain reaction tests were negative. She underwent CT scan of neck, chest, abdomen and pelvis, mammogram, stool occult blood, carcinoembryonic antigen, CA-125, and Ca 19–9 tests, all of which were non-contributory to any occult malignancy. Thrombophilia screening was not done at this acute stage. We decided to get those done after the completion of anticoagulant treatment. She showed good clinical improvement over the course of the next few days. A repeat CT scan of the head done on day seven, revealed decreasing edema and stable hematoma volume with no new bleeding. The cause of her CVST was deemed undermined at this stage and she was discharged home on dabigatran 150 mg twice daily, as she could not get PT/INR done reliably due to the current lockdown imposed by the government. She has been doing well on follow up.

A 38-year-old woman on oral contraceptives presented with headache and difficulty speaking. She had no other significant past medical history. A left frontal SDH and left temporal venous infarct with a left transverse sinus thrombosis was demonstrated on CT and MRI []. A hypercoagulable work-up did not reveal any additional thrombophilias. She was initially managed with systemic anticoagulation using intravenous heparin. After serial neurologic examinations and repeat CT, head imaging demonstrated no further bleeding; she was transitioned to oral warfarin and discharged home. She had excellent neurologic recovery (modified Rankin score 0) at 3 months follow up visit.

Write a detailed clinical case vignette based on the following key phrases: Subdural Hematoma, Cerebral Venous Thrombosis, Dural Arteriovenous Fistula

A 38-year-old woman on oral contraceptives presented with headache and difficulty speaking. She had no other significant past medical history. A left frontal SDH and left temporal venous infarct with a left transverse sinus thrombosis was demonstrated on CT and MRI []. A hypercoagulable work-up did not reveal any additional thrombophilias. She was initially managed with systemic anticoagulation using intravenous heparin. After serial neurologic examinations and repeat CT, head imaging demonstrated no further bleeding; she was transitioned to oral warfarin and discharged home. She had excellent neurologic recovery (modified Rankin score 0) at 3 months follow up visit.

A 77-year-old male with a recent syncope-related fall and closed head injury presented with gradually worsening isolated right upper extremity monoparesis. The fall occurred 1 month before presentation. On examination, the patient demonstrated 4/5 strength in his right upper extremity, with no additional neurologic deficits. Noncontrast head CT demonstrated bilateral mixed density convexity subdural hematomas [22 mm on the left and 14 mm on the right; and ]. The patient underwent a left craniotomy for evacuation of the larger hematoma, in conjunction with bilateral MMA embolization as primary treatment for the right convexity subdural hematoma in addition to limiting potential recurrence along the left convexity. Intraprocedural digital subtraction angiogram revealed two Cognard Grade III DAVFs, one arising from the parietal branch of the right MMA draining into an occipital cortical vein, and the second arising from the temporal branch of the left MMA draining into the vein of Labbe [-]. Given the presence of cortical venous reflux and associated risk of future intracranial hemorrhage, treatment of the fistulae was indicated. This was approached in two staged procedures. Following an uncomplicated left MMA embolization (frontoparietal branch), the incidental findings were discussed with the patient and he underwent a second stage embolization for the DAVF on a later date. During the second stage, a more prolonged infusion of liquid embolic was employed to ensure penetration into the recipient cortical venous outflow, resulting in nonopacification of the aforementioned fistulae. The postoperative course was complicated by seizures which resolved with uptitration in antiepileptic medications. At 6-month follow-up, there was complete resolution of the patient’s presenting symptoms and surveillance CT demonstrated no residual SDH.

Write a detailed clinical case vignette based on the following key phrases: Subdural Hematoma, Cerebral Venous Thrombosis, Dural Arteriovenous Fistula

A 60-year-old male experienced one month of escalating bifrontal headaches refractory to analgesics and antibiotics prescribed for presumed sinusitis. The headaches increased during sneezing, bending over, or bedrest and improved when he was sitting or standing. There was no history of trauma. His prior medical history was notable for hypertension and hyperlipidemia. There was no family history of coagulopathy or thrombophilia. He was married, employed, used 0.5 packs of tobacco (7.5 packs/years), consumed alcohol socially, and did not use any illicit drugs. His vital signs were notable for sinus bradycardia with a heart rate of 39 and elevated BP of 184/86 mmHg. He had no other significant findings on physical examination; detailed neurologic examination was unremarkable. Routine admission laboratory studies were within normal limits. Coagulation studies including platelet function assays were normal.\nNoncontrasted head CT demonstrated a 19 mm left isodense SDH with 10 mm of midline shift []. The collection was more prominent in the frontal region. A CT angiogram was obtained prior to surgery, and no source of bleeding was identified. He underwent a mini-craniotomy; and repeat CT imaging after the procedure [] demonstrated excellent hematoma evacuation and brain reexpansion.\nA scheduled follow up head CT obtained on postoperative day 27 was notable for recurrent SDH with a frontal predilection \n[]. The appearance and location were similar to the initial presentation. He was readmitted to the hospital and underwent SDH drainage via burr hole. On subsequent imaging with MRI, MR angiography, and MR venography, a filling defect was visible in the distal left transverse sinus and no flow was observed in the distal left sigmoid sinus or internal jugular vein. These findings were confirmed on CT venography.\nPatient underwent cerebral angiography on postoperative day 7 after SDH evacuation []. Left carotid injection was notable for a prominent left vein of Labbe with delayed wash-out, a filling defect in the left transverse sinus, and retrograde flow in the left transverse sinus with subsequent drainage into the right transverse sinus. Transvenous catheterization confirmed retrograde drainage of the left transverse sinus and venous stasis in the left vein of Labbe. Manometric readings in the left sigmoid sinus and both transverse sinuses were elevated (18-25 mmHg range). Thrombectomy with the Penumbra device and venoplasty with 7 × 20 mm balloon were performed; 10 mg of systemic abciximab was administered. Follow up venography demonstrated improved flow in the left vein of Labbe, restored normal direction of flow in the sinuses with normalized pressure (11 mmHg) in the left transverse sinus. Daily aspirin (325 mg) was initiated on the day of this intervention; patient was discharged home without neurologic deficits. A follow-up CT venogram at 6 weeks demonstrated patent venous sinuses and no recurrence of his SDH. His 3 month clinical outcome was excellent (modified Rankin score 0).

A 38-year-old woman on oral contraceptives presented with headache and difficulty speaking. She had no other significant past medical history. A left frontal SDH and left temporal venous infarct with a left transverse sinus thrombosis was demonstrated on CT and MRI []. A hypercoagulable work-up did not reveal any additional thrombophilias. She was initially managed with systemic anticoagulation using intravenous heparin. After serial neurologic examinations and repeat CT, head imaging demonstrated no further bleeding; she was transitioned to oral warfarin and discharged home. She had excellent neurologic recovery (modified Rankin score 0) at 3 months follow up visit.

Write a detailed clinical case vignette based on the following key phrases: Subdural Hematoma, Cerebral Venous Thrombosis, Dural Arteriovenous Fistula

A 38-year-old woman on oral contraceptives presented with headache and difficulty speaking. She had no other significant past medical history. A left frontal SDH and left temporal venous infarct with a left transverse sinus thrombosis was demonstrated on CT and MRI []. A hypercoagulable work-up did not reveal any additional thrombophilias. She was initially managed with systemic anticoagulation using intravenous heparin. After serial neurologic examinations and repeat CT, head imaging demonstrated no further bleeding; she was transitioned to oral warfarin and discharged home. She had excellent neurologic recovery (modified Rankin score 0) at 3 months follow up visit.

A 59-year-old male with a recent fall and closed head injury presented with progressively worsening headaches. The fall occurred 9 days before presentation. On examination, no neurologic deficits were found. Noncontrast head CT demonstrated a 5 mm left convexity CSDH []. He underwent burr hole evacuation and was discharged on the subsequent day. He presented again on postoperative day 6 with recurrence of his headaches. Noncontrast head CT demonstrated recurrence of the left convexity subdural hematoma []. He subsequently underwent a left craniotomy for evacuation. He was discharged on postoperative day 2 with no postprocedural complications. At 1-month follow-up, he continued to complain of severe headaches. Surveillance CT demonstrated a new 27 mm right convexity mixed density subdural hematoma [ and ]. He subsequently underwent right MMA embolization as primary treatment. Intraprocedural digital subtraction angiogram revealed a Cognard Grade III cribriform plate DAVF supplied by the right ophthalmic artery draining into a right frontal cortical vein [ and ]. The right MMA temporoparietal and frontal branches were embolized with n-BCA glue. Follow-up was arranged to treat the DAVF at a later date and he was discharged the following day. The patient was subsequently lost to follow-up, but presented to the emergency department 4 months later with diplopia and a right abducens nerve palsy. Noncontrast head CT demonstrated significant reduction in size of the previously embolized right convexity subdural hematoma. He was admitted and underwent attempted endovascular treatment of the DAVF. Catheterization of the arterial and venous sides of the fistula achieved suboptimal positioning for liquid embolic embolization and so he underwent a right craniotomy for surgical ligation of the fistula. The patient experienced no postprocedural complications. At 2-week follow-up, there was complete resolution of his presenting symptoms and surveillance CT demonstrated no residual SDH.

Write a detailed clinical case vignette based on the following key phrases: Subdural Hematoma, Cerebral Venous Thrombosis, Dural Arteriovenous Fistula

A 38-year-old woman on oral contraceptives presented with headache and difficulty speaking. She had no other significant past medical history. A left frontal SDH and left temporal venous infarct with a left transverse sinus thrombosis was demonstrated on CT and MRI []. A hypercoagulable work-up did not reveal any additional thrombophilias. She was initially managed with systemic anticoagulation using intravenous heparin. After serial neurologic examinations and repeat CT, head imaging demonstrated no further bleeding; she was transitioned to oral warfarin and discharged home. She had excellent neurologic recovery (modified Rankin score 0) at 3 months follow up visit.

A 68-year-old woman with polycythemia vera experienced a global, nonpositional headache for one day. She subsequently became comatose. On emergent evaluation she exhibited decorticate posturing. Her Glasgow coma score was 6. There was no preceding history of trauma, infection, or dehydration. She was not on anticoagulants or antiplatelet agents. Her polycythemia vera had been managed with therapeutic phlebotomy and hydroxyurea (500 mg daily). She had no prior history of thromboembolic events. Noncontrasted head CT showed extensive left 20 mm acute SDH with 16 mm of midline shift []. She underwent emergent craniotomy and hematoma evacuation. On careful inspection of the exposed brain, a prominent and engorged cortical vein observed. No other vascular abnormalities or potential bleeding sources were identified. CT venography and MR venography detected partial superior sagittal sinus thrombosis, which leads to the empty delta sign (the intraluminal thrombus prevents central filling of the sinus; ). She was managed conservatively with hydroxyurea, hydration, and aspirin. Laboratory analyses were notable for normal coagulation panel, normal platelet function assays, hematocrit of 45.9, negative thrombophilia evaluation (protein S, protein C, antithrombin III, anticardiolipin antibody, homocysteine, lupus anticoagulant, beta-2 glycoprotein antibodies, Factor V Leiden mutation, prothrombin gene mutation). Analysis of DNA extracted from her blood revealed the presence of the V617F mutation within the JAK2 gene. Her 3-month outcome was poor (modified Rankin score 4).

Write a detailed clinical case vignette based on the following key phrases: Subdural Hematoma, Cerebral Venous Thrombosis, Dural Arteriovenous Fistula

A 38-year-old woman on oral contraceptives presented with headache and difficulty speaking. She had no other significant past medical history. A left frontal SDH and left temporal venous infarct with a left transverse sinus thrombosis was demonstrated on CT and MRI []. A hypercoagulable work-up did not reveal any additional thrombophilias. She was initially managed with systemic anticoagulation using intravenous heparin. After serial neurologic examinations and repeat CT, head imaging demonstrated no further bleeding; she was transitioned to oral warfarin and discharged home. She had excellent neurologic recovery (modified Rankin score 0) at 3 months follow up visit.

A 59-year-old male patient suffered from rapidly progressive and pulsatile headache over the right parietal region characterized as thunderclap and nausea. He had no fever. These symptoms were followed by generalized seizure. Neurological examination showed a normal level of consciousness. On examination, meningism was seen. The rest of the physical examination was unremarkable. CT scan head was normal. MRI revealed right parasagittal high fronto-parietal subarachnoid hemorrhage with mild gyral edema. MRV showed superior sagittal sinus and bilateral transverse sinus thrombosis [Figures and ]. DSA confirmed [Figures and ] the diagnosis of DST without any potential cause of SAH. Coagulation testing, including prothrombin time, activated prothrombin time, anticardiolipin antibody titer, antiphospholipid antibody titer, homocysteine titer, and levels of protein C and S, antithrombin III, and fibrinogen were all within normal limits and done simultaneously with MRI, MR Venography, DSA within one to two days of admission. Subcutaneous LMW heparin therapy was given. The patient's condition stabilized after nine days of treatment. Oral warfarin maintained an INR of 2.0-3.0. Patient's improvement was clinically satisfactory within six weeks, Repeat DSA done after six weeks was normal, except minimal filling defect. Patient was followed up at two-weeks intervals for three months

Write a detailed clinical case vignette based on the following key phrases: Subdural Hematoma, Cerebral Venous Thrombosis, Dural Arteriovenous Fistula

A 45-year-old man was admitted for a progressively worsening headache over 2 weeks. He denied history of recent head trauma or anticoagulation and antiplatelet medication. General and neurologic examinations were not remarkable on admission. Routine laboratory investigations including coagulation profiles and platelet function were within normal limits. Head computed tomography (CT) on admission revealed an isodense CSDH on the right hemisphere with mild midline shift (Fig. a). A CT angiography (CTA) was performed to rule out any intracranial vascular malformation. A DAVF was noticed at the transverse sinus with dilated cortical venous drainage (Fig. b). So, a digital subtraction angiography (DSA) of the external carotid artery and DAVF embolization was planned.\nNo anomaly was noticed during selective angiography of the internal carotid and vertebral arteries and the left external carotid artery. Selective angiography of the right external carotid artery showed that the DAVF was located at the transverse sinus and fed by posterior branch of the middle meningeal artery (MMA), the occipital artery, and the posterior meningeal artery and drained to the occipital cortical veins with venous ectasia (Fig. a-b). The DAVF was classified as type IV according to the Cognard classification. The embolization was performed via the MMA. The Headway duo catheter was used and accessed to the DAVF, and Onyx was injected until the shunt disappeared (Fig. c-d). The patient experienced an uneventful recovery. His CSDH gradually resolved in 1 month (Fig. ). No neurologic deficit was noticed.\nA PubMed search of published studies written in English and Chinese was conducted on June 30th, 2017. The following key words were used in relevant combinations: dural arteriovenous fistula, dural arteriovenous malformation, subdural hematoma, subdural haematoma, subdural hemorrhage, and subdural haemorrhage. The reference lists of the identified articles were also manually searched for additional studies. Studies of which full text could not be obtained or those without sufficient individualized description of the isolated SDH cases mixed in larger case series were excluded.\nFinally, 13 articles containing 14 patients were identified [–]. In all 15 patients (9 females, 60%) including 1 case in our institution were included for the final interpretation (Table ). The inflicted patients were aged from 27 to 82 years (55.5 ± 8.6).Of note, 12 (80%) of the 15 patients were aged between 40 and 60 years of age, and 8 (53.3%) patients were between 50 and 60 years. Sides of the DAVF or SDH were obtained in 13 patients with 9 (69.2%) located at the left side and 4 at the right side. The intracranial locations of DAVF were anterior fossa (2), middle fossa (2), frontal region (2), parietal region (3), temporal region (2), and occipital region (2). The types of SDH were CSDH (7/15), acute SDH (ASDH) (7/15), and undefined SDH (1/15). Of the 12 patients feeding artery could be identified, MMA was the commonest feeding artery (8/12, 66.7%). Multiple feeding arteries were identified in 3 (25%) patients. The causes of DAVF were only defined in 3 patients (2 iatrogenic and 1 traumatic), with the rest undefined or not mentioned. Cognard classifications (Table ) of the DAVF were reported or deduced from the reports in 12 patients, with type I, type III, and type IV in 7, 2, and 3 patients respectively. The treatment strategies included hematoma evacuation (2/15), CSDH drainage and DAVF embolization (5/15), craniotomy and DAVF resection (3/15), DAVF embolization and hematoma evacuation (1/15), DAVF embolization (2/15), and not applicable or not mentioned (2/15). Of the 12 patients with direct description of outcome, 7 (58.3%) patients were neurological intact, 3 (25%) patients with neurological deficits, and 2 (16.7%) died.

We report a case of a 23-year-old male, known case of Down’s syndrome, who presented to our Emergency Department with a complaint of severe headache for three days. It was accompanied by nausea, vomiting, and confusion. There was no history of trauma, seizures, loss of consciousness, change in vision, or relevant signs of virus infection. He was not on any regular medications. His medical background included surgical closure of ventricular septal defects in his childhood. There was no past medical or family history of coagulopathies.\nOn examination, his Glasgow coma score was 14, with normal vital signs. On neurological examination, the patient was confused, with dense right-sided hemiparesis. Liver function test, prothrombin time, partial thromboplastin time, and international normalized ratio were all within normal range. The brain CT scan revealed left-sided subacute SDH with a 12 mm midline shift and uncal herniation ().\nThe patient underwent emergent left-sided craniotomy and SDH evacuation. The blood evacuated was a mixture of dark stained blood and clots. Post-surgery, the patient’s consciousness level returned to normal, and he regained full power in all limbs. His post-operative CT scan showed optimal evacuation of the left-sided hematoma. There was also a new finding of a small right-sided SDH in the parietal region with no significant mass effect (). The CT scans review showed hyperdense areas in the transverse and sigmoid sinus; this raised suspicion of thrombosis. Magnetic resonance venography (MRV) confirmed the diagnosis of CVST in the right transverse and sigmoid sinuses with loss of flow signal ().\nClinically, the patient made an excellent post-operative recovery. After the diagnosis of CVST, we obtained neurology opinion and considered it risky to commence therapeutic anticoagulation in the early post-operative phase. He was started on a prophylactic dose of low molecular heparin. The patient was discharged home one week after surgery. Subsequently, he was readmitted electively two weeks later and was commenced on Apixaban. He was followed up regularly in outpatients and was asymptomatic.\nThe patient re-presented three months later complaining of a headache and recurrent vomiting, with normal consciousness levels. His repeat brain CT showed recollection of hematoma in the left subdural space (). An updated MRV revealed an interval shrinkage of the thrombus in the right sigmoid venous sinus; however, the reduced flow was seen through the sinus. The medical decision was to stop the anticoagulation, and the patient underwent reopening of the left-sided craniotomy and evacuation of the recurrent SDH. He recovered well after surgery, and we elected not to restart anticoagulation and follow-him clinically.\nThe patient remains clinically well. Interval MRI and MRV scans at six months show complete resolution of the SDH, with residual partial thrombosis of the right sigmoid sinus; however, the sinus is patent, and the venous flow is restored ().

Write a detailed clinical case vignette based on the following key phrases: Subdural Hematoma, Cerebral Venous Thrombosis, Dural Arteriovenous Fistula

A 45-year-old man was admitted for a progressively worsening headache over 2 weeks. He denied history of recent head trauma or anticoagulation and antiplatelet medication. General and neurologic examinations were not remarkable on admission. Routine laboratory investigations including coagulation profiles and platelet function were within normal limits. Head computed tomography (CT) on admission revealed an isodense CSDH on the right hemisphere with mild midline shift (Fig. a). A CT angiography (CTA) was performed to rule out any intracranial vascular malformation. A DAVF was noticed at the transverse sinus with dilated cortical venous drainage (Fig. b). So, a digital subtraction angiography (DSA) of the external carotid artery and DAVF embolization was planned.\nNo anomaly was noticed during selective angiography of the internal carotid and vertebral arteries and the left external carotid artery. Selective angiography of the right external carotid artery showed that the DAVF was located at the transverse sinus and fed by posterior branch of the middle meningeal artery (MMA), the occipital artery, and the posterior meningeal artery and drained to the occipital cortical veins with venous ectasia (Fig. a-b). The DAVF was classified as type IV according to the Cognard classification. The embolization was performed via the MMA. The Headway duo catheter was used and accessed to the DAVF, and Onyx was injected until the shunt disappeared (Fig. c-d). The patient experienced an uneventful recovery. His CSDH gradually resolved in 1 month (Fig. ). No neurologic deficit was noticed.\nA PubMed search of published studies written in English and Chinese was conducted on June 30th, 2017. The following key words were used in relevant combinations: dural arteriovenous fistula, dural arteriovenous malformation, subdural hematoma, subdural haematoma, subdural hemorrhage, and subdural haemorrhage. The reference lists of the identified articles were also manually searched for additional studies. Studies of which full text could not be obtained or those without sufficient individualized description of the isolated SDH cases mixed in larger case series were excluded.\nFinally, 13 articles containing 14 patients were identified [–]. In all 15 patients (9 females, 60%) including 1 case in our institution were included for the final interpretation (Table ). The inflicted patients were aged from 27 to 82 years (55.5 ± 8.6).Of note, 12 (80%) of the 15 patients were aged between 40 and 60 years of age, and 8 (53.3%) patients were between 50 and 60 years. Sides of the DAVF or SDH were obtained in 13 patients with 9 (69.2%) located at the left side and 4 at the right side. The intracranial locations of DAVF were anterior fossa (2), middle fossa (2), frontal region (2), parietal region (3), temporal region (2), and occipital region (2). The types of SDH were CSDH (7/15), acute SDH (ASDH) (7/15), and undefined SDH (1/15). Of the 12 patients feeding artery could be identified, MMA was the commonest feeding artery (8/12, 66.7%). Multiple feeding arteries were identified in 3 (25%) patients. The causes of DAVF were only defined in 3 patients (2 iatrogenic and 1 traumatic), with the rest undefined or not mentioned. Cognard classifications (Table ) of the DAVF were reported or deduced from the reports in 12 patients, with type I, type III, and type IV in 7, 2, and 3 patients respectively. The treatment strategies included hematoma evacuation (2/15), CSDH drainage and DAVF embolization (5/15), craniotomy and DAVF resection (3/15), DAVF embolization and hematoma evacuation (1/15), DAVF embolization (2/15), and not applicable or not mentioned (2/15). Of the 12 patients with direct description of outcome, 7 (58.3%) patients were neurological intact, 3 (25%) patients with neurological deficits, and 2 (16.7%) died.

A 40-year-old female presented to an emergency in altered sensorium with right hemiplegia with a history of a severe headache and multiple episodes of vomiting 1 day prior to admission. She was on oral contraceptives for last 2 years. Her Glasgow Coma Scale at admission was E1M3V1 and left pupil was dilated and not reacting to light. Computed tomography (CT) of head revealed venous infarct in left temporo-occipito-parietal region with linear area of hemorrhage within it with large left fronto-temporo-parietal acute subdural hematoma with midline shift of 9 mm toward right side with subfalcine herniation with descending transtentorial herniation with sub-arachnoid hemorrhage in the left parietal and occipital sulci with diffuse cerebral edema [].\nCT venography revealed thrombosis in superior sagittal sinus extending to adjacent cortical veins []. She was immediately taken for surgery, and a left fronto-temporo-parietal decompressive craniectomy was performed with the evacuation of acute subdural hematoma and lax duroplasty. However, she continued to deteriorate in the postoperative period and died on the first postoperative day.

Write a detailed clinical case vignette based on the following key phrases: Subdural Hematoma, Cerebral Venous Thrombosis, Dural Arteriovenous Fistula

A 45-year-old man was admitted for a progressively worsening headache over 2 weeks. He denied history of recent head trauma or anticoagulation and antiplatelet medication. General and neurologic examinations were not remarkable on admission. Routine laboratory investigations including coagulation profiles and platelet function were within normal limits. Head computed tomography (CT) on admission revealed an isodense CSDH on the right hemisphere with mild midline shift (Fig. a). A CT angiography (CTA) was performed to rule out any intracranial vascular malformation. A DAVF was noticed at the transverse sinus with dilated cortical venous drainage (Fig. b). So, a digital subtraction angiography (DSA) of the external carotid artery and DAVF embolization was planned.\nNo anomaly was noticed during selective angiography of the internal carotid and vertebral arteries and the left external carotid artery. Selective angiography of the right external carotid artery showed that the DAVF was located at the transverse sinus and fed by posterior branch of the middle meningeal artery (MMA), the occipital artery, and the posterior meningeal artery and drained to the occipital cortical veins with venous ectasia (Fig. a-b). The DAVF was classified as type IV according to the Cognard classification. The embolization was performed via the MMA. The Headway duo catheter was used and accessed to the DAVF, and Onyx was injected until the shunt disappeared (Fig. c-d). The patient experienced an uneventful recovery. His CSDH gradually resolved in 1 month (Fig. ). No neurologic deficit was noticed.\nA PubMed search of published studies written in English and Chinese was conducted on June 30th, 2017. The following key words were used in relevant combinations: dural arteriovenous fistula, dural arteriovenous malformation, subdural hematoma, subdural haematoma, subdural hemorrhage, and subdural haemorrhage. The reference lists of the identified articles were also manually searched for additional studies. Studies of which full text could not be obtained or those without sufficient individualized description of the isolated SDH cases mixed in larger case series were excluded.\nFinally, 13 articles containing 14 patients were identified [–]. In all 15 patients (9 females, 60%) including 1 case in our institution were included for the final interpretation (Table ). The inflicted patients were aged from 27 to 82 years (55.5 ± 8.6).Of note, 12 (80%) of the 15 patients were aged between 40 and 60 years of age, and 8 (53.3%) patients were between 50 and 60 years. Sides of the DAVF or SDH were obtained in 13 patients with 9 (69.2%) located at the left side and 4 at the right side. The intracranial locations of DAVF were anterior fossa (2), middle fossa (2), frontal region (2), parietal region (3), temporal region (2), and occipital region (2). The types of SDH were CSDH (7/15), acute SDH (ASDH) (7/15), and undefined SDH (1/15). Of the 12 patients feeding artery could be identified, MMA was the commonest feeding artery (8/12, 66.7%). Multiple feeding arteries were identified in 3 (25%) patients. The causes of DAVF were only defined in 3 patients (2 iatrogenic and 1 traumatic), with the rest undefined or not mentioned. Cognard classifications (Table ) of the DAVF were reported or deduced from the reports in 12 patients, with type I, type III, and type IV in 7, 2, and 3 patients respectively. The treatment strategies included hematoma evacuation (2/15), CSDH drainage and DAVF embolization (5/15), craniotomy and DAVF resection (3/15), DAVF embolization and hematoma evacuation (1/15), DAVF embolization (2/15), and not applicable or not mentioned (2/15). Of the 12 patients with direct description of outcome, 7 (58.3%) patients were neurological intact, 3 (25%) patients with neurological deficits, and 2 (16.7%) died.

A 25-year-old primigravida with a history of pre-eclampsia was brought to the emergency department with sudden onset of severe headache. The headache started two days after delivery. It was followed by confusion and loss of consciousness over a few hours. On initial evaluation, the patient was confused with a Glasgow Coma Scale (GCS) of 12/15, blood pressure of 130/90 mmHg, pulse rate of 82 beats/min, respiratory rate of 30/min, temperature 98°C, and oxygen saturation of 97 mmHg at room temperature. On physical examination, bilateral equivocal planters were noted with no other significant findings, and bilateral papillary edema on fundoscopy was seen. The rest of the review system was unremarkable. She underwent an urgent MRI with magnetic resonance venography (MRV) of the brain, which showed right transverse sinus thrombosis with an element of SAH (Figure ).\nCoagulation profile, including thrombin time (TT), prothrombin time (PT), partial thromboplastin time (PTT), antithrombin III, fibrinogen, proteins C and S, antiphospholipid antibody titers, and homocysteine levels, were normal. She was started on a half dosage of low molecular weight heparin (LMWH) (60 mg subcutaneously once a day) with regular monitoring of her blood pressure and GCS. Her GCS started improving; therefore, she was continued on a half dose of LMWH for 10 days, and brain MRI was repeated after 10 days, which showed the gradual resolution of SAH (Figure ). The quantity of LMWH was doubled, and warfarin was started after a full dose of LMWH. After improving her GCS and achievement of international normalized ratio (INR) of two to three, she was discharged with the advice of regular INR monitoring and follow-up to the outpatient department. On follow-up at six weeks, MRI with MRV was repeated, which showed thrombosis had resolved, although a mild filling defect was noted. She was kept on anticoagulants for one year, and on further follow-up at six months, she was doing well.

Write a detailed clinical case vignette based on the following key phrases: Subdural Hematoma, Cerebral Venous Thrombosis, Dural Arteriovenous Fistula

A 45-year-old man was admitted for a progressively worsening headache over 2 weeks. He denied history of recent head trauma or anticoagulation and antiplatelet medication. General and neurologic examinations were not remarkable on admission. Routine laboratory investigations including coagulation profiles and platelet function were within normal limits. Head computed tomography (CT) on admission revealed an isodense CSDH on the right hemisphere with mild midline shift (Fig. a). A CT angiography (CTA) was performed to rule out any intracranial vascular malformation. A DAVF was noticed at the transverse sinus with dilated cortical venous drainage (Fig. b). So, a digital subtraction angiography (DSA) of the external carotid artery and DAVF embolization was planned.\nNo anomaly was noticed during selective angiography of the internal carotid and vertebral arteries and the left external carotid artery. Selective angiography of the right external carotid artery showed that the DAVF was located at the transverse sinus and fed by posterior branch of the middle meningeal artery (MMA), the occipital artery, and the posterior meningeal artery and drained to the occipital cortical veins with venous ectasia (Fig. a-b). The DAVF was classified as type IV according to the Cognard classification. The embolization was performed via the MMA. The Headway duo catheter was used and accessed to the DAVF, and Onyx was injected until the shunt disappeared (Fig. c-d). The patient experienced an uneventful recovery. His CSDH gradually resolved in 1 month (Fig. ). No neurologic deficit was noticed.\nA PubMed search of published studies written in English and Chinese was conducted on June 30th, 2017. The following key words were used in relevant combinations: dural arteriovenous fistula, dural arteriovenous malformation, subdural hematoma, subdural haematoma, subdural hemorrhage, and subdural haemorrhage. The reference lists of the identified articles were also manually searched for additional studies. Studies of which full text could not be obtained or those without sufficient individualized description of the isolated SDH cases mixed in larger case series were excluded.\nFinally, 13 articles containing 14 patients were identified [–]. In all 15 patients (9 females, 60%) including 1 case in our institution were included for the final interpretation (Table ). The inflicted patients were aged from 27 to 82 years (55.5 ± 8.6).Of note, 12 (80%) of the 15 patients were aged between 40 and 60 years of age, and 8 (53.3%) patients were between 50 and 60 years. Sides of the DAVF or SDH were obtained in 13 patients with 9 (69.2%) located at the left side and 4 at the right side. The intracranial locations of DAVF were anterior fossa (2), middle fossa (2), frontal region (2), parietal region (3), temporal region (2), and occipital region (2). The types of SDH were CSDH (7/15), acute SDH (ASDH) (7/15), and undefined SDH (1/15). Of the 12 patients feeding artery could be identified, MMA was the commonest feeding artery (8/12, 66.7%). Multiple feeding arteries were identified in 3 (25%) patients. The causes of DAVF were only defined in 3 patients (2 iatrogenic and 1 traumatic), with the rest undefined or not mentioned. Cognard classifications (Table ) of the DAVF were reported or deduced from the reports in 12 patients, with type I, type III, and type IV in 7, 2, and 3 patients respectively. The treatment strategies included hematoma evacuation (2/15), CSDH drainage and DAVF embolization (5/15), craniotomy and DAVF resection (3/15), DAVF embolization and hematoma evacuation (1/15), DAVF embolization (2/15), and not applicable or not mentioned (2/15). Of the 12 patients with direct description of outcome, 7 (58.3%) patients were neurological intact, 3 (25%) patients with neurological deficits, and 2 (16.7%) died.

This 67-year-old male man has had a progressively worsening pain on the left cranium over 2 weeks that intractable to some analgesics. There was no recent head trauma or other medical disease in his history. On admission, the general physical and neurologic investigations were not remarkable. Routine laboratory evaluations including coagulation profiles and platelet function were within normal limits.\nBrain computed tomography (CT) scans revealed an isodense left-sided CSDH with marked cerebral shifting (). There was no evidence of source of this hemorrhage with temporal predilection on the CT angiogram. On magnetic resonance (MR) image subsequently obtained, the abnormal intensity within the subarachnoid space and the brain parenchyma was not visible. The patency without steno-occlusion in both transverse and sigmoid sinuses was clearly delineated on T2-weighted sequences (). This patient has received a trephination and SDH drainage, after that he was sent home with resolution of headache. Approximately 2 weeks later, however, he developed an excruciating pain in the temporal and parietal regions with recurrence of subdural collection. The site and density of hematoma was similar to the first presentation (). He was immediately returned for subdural irrigation and decompression through the prior burr-holes. The patient's clinical course was not eventful, but he complained of a mild headache again. Follow-up CT scanned just prior to discharge was strikingly for the newly-formed thin hematoma at the operative site (). Another evacuation of this subacute subdural clot was not deemed to be necessary.\nAt this time, an active intervention was sought for this patient who had an intractably recurring CSDH. On the 7th day after the second surgery, angiography was performed to rule out an occult vascular lesion. A flow-guided type microcatheter (Prowler 10™, Cordis Neurovascular, Miami Lakes, FL, USA) was positioned in the main trunk of the MMA for selective angiography. The frontal and parietal branch of the MMA was appeared normally, and the abnormal membrane staining on the affected side was not detected. A left external carotid angiogram disclosed a dural AVF between the petrosquamosal branch of the MMA and the transverse-sigmoid sinus without retrograde cortical venous draining. The AV shunt had no connection to the internal carotid artery and its branches. It was suggested that the bleeding from the draining venous system of the dural AVF led to refractory CSDH. The microcatheter was introduced into the petrosquamosal branch of the MMA, thereafter polyvinyl alcohol particles ranging 150 to 250 µm were distally injected (). After trans-arterial obliteration of the feeder and fistula, the AV shunt disappeared. The recurrent hematoma of this patient did not increase, and his complaints of headache gradually subsided. The brain CT at one year following the embolization therapy revealed complete regression of the subdural hematomas ().

Write a detailed clinical case vignette based on the following key phrases: Subdural Hematoma, Cerebral Venous Thrombosis, Dural Arteriovenous Fistula

A 45-year-old man was admitted for a progressively worsening headache over 2 weeks. He denied history of recent head trauma or anticoagulation and antiplatelet medication. General and neurologic examinations were not remarkable on admission. Routine laboratory investigations including coagulation profiles and platelet function were within normal limits. Head computed tomography (CT) on admission revealed an isodense CSDH on the right hemisphere with mild midline shift (Fig. a). A CT angiography (CTA) was performed to rule out any intracranial vascular malformation. A DAVF was noticed at the transverse sinus with dilated cortical venous drainage (Fig. b). So, a digital subtraction angiography (DSA) of the external carotid artery and DAVF embolization was planned.\nNo anomaly was noticed during selective angiography of the internal carotid and vertebral arteries and the left external carotid artery. Selective angiography of the right external carotid artery showed that the DAVF was located at the transverse sinus and fed by posterior branch of the middle meningeal artery (MMA), the occipital artery, and the posterior meningeal artery and drained to the occipital cortical veins with venous ectasia (Fig. a-b). The DAVF was classified as type IV according to the Cognard classification. The embolization was performed via the MMA. The Headway duo catheter was used and accessed to the DAVF, and Onyx was injected until the shunt disappeared (Fig. c-d). The patient experienced an uneventful recovery. His CSDH gradually resolved in 1 month (Fig. ). No neurologic deficit was noticed.\nA PubMed search of published studies written in English and Chinese was conducted on June 30th, 2017. The following key words were used in relevant combinations: dural arteriovenous fistula, dural arteriovenous malformation, subdural hematoma, subdural haematoma, subdural hemorrhage, and subdural haemorrhage. The reference lists of the identified articles were also manually searched for additional studies. Studies of which full text could not be obtained or those without sufficient individualized description of the isolated SDH cases mixed in larger case series were excluded.\nFinally, 13 articles containing 14 patients were identified [–]. In all 15 patients (9 females, 60%) including 1 case in our institution were included for the final interpretation (Table ). The inflicted patients were aged from 27 to 82 years (55.5 ± 8.6).Of note, 12 (80%) of the 15 patients were aged between 40 and 60 years of age, and 8 (53.3%) patients were between 50 and 60 years. Sides of the DAVF or SDH were obtained in 13 patients with 9 (69.2%) located at the left side and 4 at the right side. The intracranial locations of DAVF were anterior fossa (2), middle fossa (2), frontal region (2), parietal region (3), temporal region (2), and occipital region (2). The types of SDH were CSDH (7/15), acute SDH (ASDH) (7/15), and undefined SDH (1/15). Of the 12 patients feeding artery could be identified, MMA was the commonest feeding artery (8/12, 66.7%). Multiple feeding arteries were identified in 3 (25%) patients. The causes of DAVF were only defined in 3 patients (2 iatrogenic and 1 traumatic), with the rest undefined or not mentioned. Cognard classifications (Table ) of the DAVF were reported or deduced from the reports in 12 patients, with type I, type III, and type IV in 7, 2, and 3 patients respectively. The treatment strategies included hematoma evacuation (2/15), CSDH drainage and DAVF embolization (5/15), craniotomy and DAVF resection (3/15), DAVF embolization and hematoma evacuation (1/15), DAVF embolization (2/15), and not applicable or not mentioned (2/15). Of the 12 patients with direct description of outcome, 7 (58.3%) patients were neurological intact, 3 (25%) patients with neurological deficits, and 2 (16.7%) died.

A 66-year-old male with a recent syncope-related fall and closed head injury presented with progressively worsening gait instability, dizziness, and headaches. The fall occurred 1 week before presentation. On examination, no focal neurologic deficits were found. Noncontrast head CT demonstrated a 7 mm right convexity mixed density subdural hematoma [ and ]. Given his significant headaches and progressive functional decline, MMA embolization was performed as primary treatment. Intraprocedural digital subtraction angiogram revealed a right parietal Cognard Grade I DAVF [ and ]. Given the absence of cortical venous reflux and benign natural history of the fistula, the remainder of the procedure did not deviate from routine MMA embolization. The right temporal and right frontoparietal branches of the MMA were embolized with n-BCA glue with indirect penetration of liquid embolic into the fistulous point. Following embolization, there was no further opacification of the fistula. The patient experienced no procedure-related complication and was discharged the subsequent day. At 1-month follow-up, there was complete resolution of his presenting symptoms and surveillance CT demonstrated no residual SDH.

Write a detailed clinical case vignette based on the following key phrases: Subdural Hematoma, Cerebral Venous Thrombosis, Dural Arteriovenous Fistula

A 45-year-old man was admitted for a progressively worsening headache over 2 weeks. He denied history of recent head trauma or anticoagulation and antiplatelet medication. General and neurologic examinations were not remarkable on admission. Routine laboratory investigations including coagulation profiles and platelet function were within normal limits. Head computed tomography (CT) on admission revealed an isodense CSDH on the right hemisphere with mild midline shift (Fig. a). A CT angiography (CTA) was performed to rule out any intracranial vascular malformation. A DAVF was noticed at the transverse sinus with dilated cortical venous drainage (Fig. b). So, a digital subtraction angiography (DSA) of the external carotid artery and DAVF embolization was planned.\nNo anomaly was noticed during selective angiography of the internal carotid and vertebral arteries and the left external carotid artery. Selective angiography of the right external carotid artery showed that the DAVF was located at the transverse sinus and fed by posterior branch of the middle meningeal artery (MMA), the occipital artery, and the posterior meningeal artery and drained to the occipital cortical veins with venous ectasia (Fig. a-b). The DAVF was classified as type IV according to the Cognard classification. The embolization was performed via the MMA. The Headway duo catheter was used and accessed to the DAVF, and Onyx was injected until the shunt disappeared (Fig. c-d). The patient experienced an uneventful recovery. His CSDH gradually resolved in 1 month (Fig. ). No neurologic deficit was noticed.\nA PubMed search of published studies written in English and Chinese was conducted on June 30th, 2017. The following key words were used in relevant combinations: dural arteriovenous fistula, dural arteriovenous malformation, subdural hematoma, subdural haematoma, subdural hemorrhage, and subdural haemorrhage. The reference lists of the identified articles were also manually searched for additional studies. Studies of which full text could not be obtained or those without sufficient individualized description of the isolated SDH cases mixed in larger case series were excluded.\nFinally, 13 articles containing 14 patients were identified [–]. In all 15 patients (9 females, 60%) including 1 case in our institution were included for the final interpretation (Table ). The inflicted patients were aged from 27 to 82 years (55.5 ± 8.6).Of note, 12 (80%) of the 15 patients were aged between 40 and 60 years of age, and 8 (53.3%) patients were between 50 and 60 years. Sides of the DAVF or SDH were obtained in 13 patients with 9 (69.2%) located at the left side and 4 at the right side. The intracranial locations of DAVF were anterior fossa (2), middle fossa (2), frontal region (2), parietal region (3), temporal region (2), and occipital region (2). The types of SDH were CSDH (7/15), acute SDH (ASDH) (7/15), and undefined SDH (1/15). Of the 12 patients feeding artery could be identified, MMA was the commonest feeding artery (8/12, 66.7%). Multiple feeding arteries were identified in 3 (25%) patients. The causes of DAVF were only defined in 3 patients (2 iatrogenic and 1 traumatic), with the rest undefined or not mentioned. Cognard classifications (Table ) of the DAVF were reported or deduced from the reports in 12 patients, with type I, type III, and type IV in 7, 2, and 3 patients respectively. The treatment strategies included hematoma evacuation (2/15), CSDH drainage and DAVF embolization (5/15), craniotomy and DAVF resection (3/15), DAVF embolization and hematoma evacuation (1/15), DAVF embolization (2/15), and not applicable or not mentioned (2/15). Of the 12 patients with direct description of outcome, 7 (58.3%) patients were neurological intact, 3 (25%) patients with neurological deficits, and 2 (16.7%) died.

A 58-year-old right-handed postmenopausal woman presented to the emergency with progressively increasing holocephalic headache for 3 days. She did not have fever, nausea, and vomiting. The headache gradually worsened in severity and on the day of presentation, she developed a generalized tonic clonic seizure. Apart from the history of well-controlled diabetes mellitus, she did not have significant past medical, personal, and family history. She had not received any vaccines in the recent past. On examination, she was ill-looking, but her vital signs were stable. She had Wernicke's aphasia. She did not have disc edema; cranial nerve examination was normal, and she did not have any focal deficits.\nAn urgent CT scan of the head without contrast showed left temporal hematoma with surrounding vasogenic edema (Figure ). Hemorrhagic picture was noted in the insular cistern (Figure ), left fronto-temporal subdural space (Figure ), the perimesencephalic, ambient and suprasellar cisterns (Figures and ), and the sulci of the left temporo-parietal lobes (Figures and ). There was a subtle dense clot sign in the left transverse sinus (Figure ). She was diagnosed as having left transverse sinus thrombosis leading to left temporal hematoma, SAH and SDH. She was treated with low molecular weight heparin, levetiracetam, and 3% hypertonic saline. The magnetic resonance venography (MRV) done the following day confirmed the presence of left transverse sinus thrombosis (Figure ). CT angiography of the brain did not reveal any vascular malformations. Her complete blood counts, coagulation profiles, routine blood chemistry, and C-reactive protein were within normal limits. Antinuclear antibody and SARS-CoV-2 RNA polymerase chain reaction tests were negative. She underwent CT scan of neck, chest, abdomen and pelvis, mammogram, stool occult blood, carcinoembryonic antigen, CA-125, and Ca 19–9 tests, all of which were non-contributory to any occult malignancy. Thrombophilia screening was not done at this acute stage. We decided to get those done after the completion of anticoagulant treatment. She showed good clinical improvement over the course of the next few days. A repeat CT scan of the head done on day seven, revealed decreasing edema and stable hematoma volume with no new bleeding. The cause of her CVST was deemed undermined at this stage and she was discharged home on dabigatran 150 mg twice daily, as she could not get PT/INR done reliably due to the current lockdown imposed by the government. She has been doing well on follow up.

Write a detailed clinical case vignette based on the following key phrases: Subdural Hematoma, Cerebral Venous Thrombosis, Dural Arteriovenous Fistula

A 45-year-old man was admitted for a progressively worsening headache over 2 weeks. He denied history of recent head trauma or anticoagulation and antiplatelet medication. General and neurologic examinations were not remarkable on admission. Routine laboratory investigations including coagulation profiles and platelet function were within normal limits. Head computed tomography (CT) on admission revealed an isodense CSDH on the right hemisphere with mild midline shift (Fig. a). A CT angiography (CTA) was performed to rule out any intracranial vascular malformation. A DAVF was noticed at the transverse sinus with dilated cortical venous drainage (Fig. b). So, a digital subtraction angiography (DSA) of the external carotid artery and DAVF embolization was planned.\nNo anomaly was noticed during selective angiography of the internal carotid and vertebral arteries and the left external carotid artery. Selective angiography of the right external carotid artery showed that the DAVF was located at the transverse sinus and fed by posterior branch of the middle meningeal artery (MMA), the occipital artery, and the posterior meningeal artery and drained to the occipital cortical veins with venous ectasia (Fig. a-b). The DAVF was classified as type IV according to the Cognard classification. The embolization was performed via the MMA. The Headway duo catheter was used and accessed to the DAVF, and Onyx was injected until the shunt disappeared (Fig. c-d). The patient experienced an uneventful recovery. His CSDH gradually resolved in 1 month (Fig. ). No neurologic deficit was noticed.\nA PubMed search of published studies written in English and Chinese was conducted on June 30th, 2017. The following key words were used in relevant combinations: dural arteriovenous fistula, dural arteriovenous malformation, subdural hematoma, subdural haematoma, subdural hemorrhage, and subdural haemorrhage. The reference lists of the identified articles were also manually searched for additional studies. Studies of which full text could not be obtained or those without sufficient individualized description of the isolated SDH cases mixed in larger case series were excluded.\nFinally, 13 articles containing 14 patients were identified [–]. In all 15 patients (9 females, 60%) including 1 case in our institution were included for the final interpretation (Table ). The inflicted patients were aged from 27 to 82 years (55.5 ± 8.6).Of note, 12 (80%) of the 15 patients were aged between 40 and 60 years of age, and 8 (53.3%) patients were between 50 and 60 years. Sides of the DAVF or SDH were obtained in 13 patients with 9 (69.2%) located at the left side and 4 at the right side. The intracranial locations of DAVF were anterior fossa (2), middle fossa (2), frontal region (2), parietal region (3), temporal region (2), and occipital region (2). The types of SDH were CSDH (7/15), acute SDH (ASDH) (7/15), and undefined SDH (1/15). Of the 12 patients feeding artery could be identified, MMA was the commonest feeding artery (8/12, 66.7%). Multiple feeding arteries were identified in 3 (25%) patients. The causes of DAVF were only defined in 3 patients (2 iatrogenic and 1 traumatic), with the rest undefined or not mentioned. Cognard classifications (Table ) of the DAVF were reported or deduced from the reports in 12 patients, with type I, type III, and type IV in 7, 2, and 3 patients respectively. The treatment strategies included hematoma evacuation (2/15), CSDH drainage and DAVF embolization (5/15), craniotomy and DAVF resection (3/15), DAVF embolization and hematoma evacuation (1/15), DAVF embolization (2/15), and not applicable or not mentioned (2/15). Of the 12 patients with direct description of outcome, 7 (58.3%) patients were neurological intact, 3 (25%) patients with neurological deficits, and 2 (16.7%) died.

A 77-year-old male with a recent syncope-related fall and closed head injury presented with gradually worsening isolated right upper extremity monoparesis. The fall occurred 1 month before presentation. On examination, the patient demonstrated 4/5 strength in his right upper extremity, with no additional neurologic deficits. Noncontrast head CT demonstrated bilateral mixed density convexity subdural hematomas [22 mm on the left and 14 mm on the right; and ]. The patient underwent a left craniotomy for evacuation of the larger hematoma, in conjunction with bilateral MMA embolization as primary treatment for the right convexity subdural hematoma in addition to limiting potential recurrence along the left convexity. Intraprocedural digital subtraction angiogram revealed two Cognard Grade III DAVFs, one arising from the parietal branch of the right MMA draining into an occipital cortical vein, and the second arising from the temporal branch of the left MMA draining into the vein of Labbe [-]. Given the presence of cortical venous reflux and associated risk of future intracranial hemorrhage, treatment of the fistulae was indicated. This was approached in two staged procedures. Following an uncomplicated left MMA embolization (frontoparietal branch), the incidental findings were discussed with the patient and he underwent a second stage embolization for the DAVF on a later date. During the second stage, a more prolonged infusion of liquid embolic was employed to ensure penetration into the recipient cortical venous outflow, resulting in nonopacification of the aforementioned fistulae. The postoperative course was complicated by seizures which resolved with uptitration in antiepileptic medications. At 6-month follow-up, there was complete resolution of the patient’s presenting symptoms and surveillance CT demonstrated no residual SDH.

Write a detailed clinical case vignette based on the following key phrases: Subdural Hematoma, Cerebral Venous Thrombosis, Dural Arteriovenous Fistula

A 60-year-old male experienced one month of escalating bifrontal headaches refractory to analgesics and antibiotics prescribed for presumed sinusitis. The headaches increased during sneezing, bending over, or bedrest and improved when he was sitting or standing. There was no history of trauma. His prior medical history was notable for hypertension and hyperlipidemia. There was no family history of coagulopathy or thrombophilia. He was married, employed, used 0.5 packs of tobacco (7.5 packs/years), consumed alcohol socially, and did not use any illicit drugs. His vital signs were notable for sinus bradycardia with a heart rate of 39 and elevated BP of 184/86 mmHg. He had no other significant findings on physical examination; detailed neurologic examination was unremarkable. Routine admission laboratory studies were within normal limits. Coagulation studies including platelet function assays were normal.\nNoncontrasted head CT demonstrated a 19 mm left isodense SDH with 10 mm of midline shift []. The collection was more prominent in the frontal region. A CT angiogram was obtained prior to surgery, and no source of bleeding was identified. He underwent a mini-craniotomy; and repeat CT imaging after the procedure [] demonstrated excellent hematoma evacuation and brain reexpansion.\nA scheduled follow up head CT obtained on postoperative day 27 was notable for recurrent SDH with a frontal predilection \n[]. The appearance and location were similar to the initial presentation. He was readmitted to the hospital and underwent SDH drainage via burr hole. On subsequent imaging with MRI, MR angiography, and MR venography, a filling defect was visible in the distal left transverse sinus and no flow was observed in the distal left sigmoid sinus or internal jugular vein. These findings were confirmed on CT venography.\nPatient underwent cerebral angiography on postoperative day 7 after SDH evacuation []. Left carotid injection was notable for a prominent left vein of Labbe with delayed wash-out, a filling defect in the left transverse sinus, and retrograde flow in the left transverse sinus with subsequent drainage into the right transverse sinus. Transvenous catheterization confirmed retrograde drainage of the left transverse sinus and venous stasis in the left vein of Labbe. Manometric readings in the left sigmoid sinus and both transverse sinuses were elevated (18-25 mmHg range). Thrombectomy with the Penumbra device and venoplasty with 7 × 20 mm balloon were performed; 10 mg of systemic abciximab was administered. Follow up venography demonstrated improved flow in the left vein of Labbe, restored normal direction of flow in the sinuses with normalized pressure (11 mmHg) in the left transverse sinus. Daily aspirin (325 mg) was initiated on the day of this intervention; patient was discharged home without neurologic deficits. A follow-up CT venogram at 6 weeks demonstrated patent venous sinuses and no recurrence of his SDH. His 3 month clinical outcome was excellent (modified Rankin score 0).

A 45-year-old man was admitted for a progressively worsening headache over 2 weeks. He denied history of recent head trauma or anticoagulation and antiplatelet medication. General and neurologic examinations were not remarkable on admission. Routine laboratory investigations including coagulation profiles and platelet function were within normal limits. Head computed tomography (CT) on admission revealed an isodense CSDH on the right hemisphere with mild midline shift (Fig. a). A CT angiography (CTA) was performed to rule out any intracranial vascular malformation. A DAVF was noticed at the transverse sinus with dilated cortical venous drainage (Fig. b). So, a digital subtraction angiography (DSA) of the external carotid artery and DAVF embolization was planned.\nNo anomaly was noticed during selective angiography of the internal carotid and vertebral arteries and the left external carotid artery. Selective angiography of the right external carotid artery showed that the DAVF was located at the transverse sinus and fed by posterior branch of the middle meningeal artery (MMA), the occipital artery, and the posterior meningeal artery and drained to the occipital cortical veins with venous ectasia (Fig. a-b). The DAVF was classified as type IV according to the Cognard classification. The embolization was performed via the MMA. The Headway duo catheter was used and accessed to the DAVF, and Onyx was injected until the shunt disappeared (Fig. c-d). The patient experienced an uneventful recovery. His CSDH gradually resolved in 1 month (Fig. ). No neurologic deficit was noticed.\nA PubMed search of published studies written in English and Chinese was conducted on June 30th, 2017. The following key words were used in relevant combinations: dural arteriovenous fistula, dural arteriovenous malformation, subdural hematoma, subdural haematoma, subdural hemorrhage, and subdural haemorrhage. The reference lists of the identified articles were also manually searched for additional studies. Studies of which full text could not be obtained or those without sufficient individualized description of the isolated SDH cases mixed in larger case series were excluded.\nFinally, 13 articles containing 14 patients were identified [–]. In all 15 patients (9 females, 60%) including 1 case in our institution were included for the final interpretation (Table ). The inflicted patients were aged from 27 to 82 years (55.5 ± 8.6).Of note, 12 (80%) of the 15 patients were aged between 40 and 60 years of age, and 8 (53.3%) patients were between 50 and 60 years. Sides of the DAVF or SDH were obtained in 13 patients with 9 (69.2%) located at the left side and 4 at the right side. The intracranial locations of DAVF were anterior fossa (2), middle fossa (2), frontal region (2), parietal region (3), temporal region (2), and occipital region (2). The types of SDH were CSDH (7/15), acute SDH (ASDH) (7/15), and undefined SDH (1/15). Of the 12 patients feeding artery could be identified, MMA was the commonest feeding artery (8/12, 66.7%). Multiple feeding arteries were identified in 3 (25%) patients. The causes of DAVF were only defined in 3 patients (2 iatrogenic and 1 traumatic), with the rest undefined or not mentioned. Cognard classifications (Table ) of the DAVF were reported or deduced from the reports in 12 patients, with type I, type III, and type IV in 7, 2, and 3 patients respectively. The treatment strategies included hematoma evacuation (2/15), CSDH drainage and DAVF embolization (5/15), craniotomy and DAVF resection (3/15), DAVF embolization and hematoma evacuation (1/15), DAVF embolization (2/15), and not applicable or not mentioned (2/15). Of the 12 patients with direct description of outcome, 7 (58.3%) patients were neurological intact, 3 (25%) patients with neurological deficits, and 2 (16.7%) died.

Write a detailed clinical case vignette based on the following key phrases: Subdural Hematoma, Cerebral Venous Thrombosis, Dural Arteriovenous Fistula

A 45-year-old man was admitted for a progressively worsening headache over 2 weeks. He denied history of recent head trauma or anticoagulation and antiplatelet medication. General and neurologic examinations were not remarkable on admission. Routine laboratory investigations including coagulation profiles and platelet function were within normal limits. Head computed tomography (CT) on admission revealed an isodense CSDH on the right hemisphere with mild midline shift (Fig. a). A CT angiography (CTA) was performed to rule out any intracranial vascular malformation. A DAVF was noticed at the transverse sinus with dilated cortical venous drainage (Fig. b). So, a digital subtraction angiography (DSA) of the external carotid artery and DAVF embolization was planned.\nNo anomaly was noticed during selective angiography of the internal carotid and vertebral arteries and the left external carotid artery. Selective angiography of the right external carotid artery showed that the DAVF was located at the transverse sinus and fed by posterior branch of the middle meningeal artery (MMA), the occipital artery, and the posterior meningeal artery and drained to the occipital cortical veins with venous ectasia (Fig. a-b). The DAVF was classified as type IV according to the Cognard classification. The embolization was performed via the MMA. The Headway duo catheter was used and accessed to the DAVF, and Onyx was injected until the shunt disappeared (Fig. c-d). The patient experienced an uneventful recovery. His CSDH gradually resolved in 1 month (Fig. ). No neurologic deficit was noticed.\nA PubMed search of published studies written in English and Chinese was conducted on June 30th, 2017. The following key words were used in relevant combinations: dural arteriovenous fistula, dural arteriovenous malformation, subdural hematoma, subdural haematoma, subdural hemorrhage, and subdural haemorrhage. The reference lists of the identified articles were also manually searched for additional studies. Studies of which full text could not be obtained or those without sufficient individualized description of the isolated SDH cases mixed in larger case series were excluded.\nFinally, 13 articles containing 14 patients were identified [–]. In all 15 patients (9 females, 60%) including 1 case in our institution were included for the final interpretation (Table ). The inflicted patients were aged from 27 to 82 years (55.5 ± 8.6).Of note, 12 (80%) of the 15 patients were aged between 40 and 60 years of age, and 8 (53.3%) patients were between 50 and 60 years. Sides of the DAVF or SDH were obtained in 13 patients with 9 (69.2%) located at the left side and 4 at the right side. The intracranial locations of DAVF were anterior fossa (2), middle fossa (2), frontal region (2), parietal region (3), temporal region (2), and occipital region (2). The types of SDH were CSDH (7/15), acute SDH (ASDH) (7/15), and undefined SDH (1/15). Of the 12 patients feeding artery could be identified, MMA was the commonest feeding artery (8/12, 66.7%). Multiple feeding arteries were identified in 3 (25%) patients. The causes of DAVF were only defined in 3 patients (2 iatrogenic and 1 traumatic), with the rest undefined or not mentioned. Cognard classifications (Table ) of the DAVF were reported or deduced from the reports in 12 patients, with type I, type III, and type IV in 7, 2, and 3 patients respectively. The treatment strategies included hematoma evacuation (2/15), CSDH drainage and DAVF embolization (5/15), craniotomy and DAVF resection (3/15), DAVF embolization and hematoma evacuation (1/15), DAVF embolization (2/15), and not applicable or not mentioned (2/15). Of the 12 patients with direct description of outcome, 7 (58.3%) patients were neurological intact, 3 (25%) patients with neurological deficits, and 2 (16.7%) died.

A 59-year-old male with a recent fall and closed head injury presented with progressively worsening headaches. The fall occurred 9 days before presentation. On examination, no neurologic deficits were found. Noncontrast head CT demonstrated a 5 mm left convexity CSDH []. He underwent burr hole evacuation and was discharged on the subsequent day. He presented again on postoperative day 6 with recurrence of his headaches. Noncontrast head CT demonstrated recurrence of the left convexity subdural hematoma []. He subsequently underwent a left craniotomy for evacuation. He was discharged on postoperative day 2 with no postprocedural complications. At 1-month follow-up, he continued to complain of severe headaches. Surveillance CT demonstrated a new 27 mm right convexity mixed density subdural hematoma [ and ]. He subsequently underwent right MMA embolization as primary treatment. Intraprocedural digital subtraction angiogram revealed a Cognard Grade III cribriform plate DAVF supplied by the right ophthalmic artery draining into a right frontal cortical vein [ and ]. The right MMA temporoparietal and frontal branches were embolized with n-BCA glue. Follow-up was arranged to treat the DAVF at a later date and he was discharged the following day. The patient was subsequently lost to follow-up, but presented to the emergency department 4 months later with diplopia and a right abducens nerve palsy. Noncontrast head CT demonstrated significant reduction in size of the previously embolized right convexity subdural hematoma. He was admitted and underwent attempted endovascular treatment of the DAVF. Catheterization of the arterial and venous sides of the fistula achieved suboptimal positioning for liquid embolic embolization and so he underwent a right craniotomy for surgical ligation of the fistula. The patient experienced no postprocedural complications. At 2-week follow-up, there was complete resolution of his presenting symptoms and surveillance CT demonstrated no residual SDH.

Write a detailed clinical case vignette based on the following key phrases: Subdural Hematoma, Cerebral Venous Thrombosis, Dural Arteriovenous Fistula

A 45-year-old man was admitted for a progressively worsening headache over 2 weeks. He denied history of recent head trauma or anticoagulation and antiplatelet medication. General and neurologic examinations were not remarkable on admission. Routine laboratory investigations including coagulation profiles and platelet function were within normal limits. Head computed tomography (CT) on admission revealed an isodense CSDH on the right hemisphere with mild midline shift (Fig. a). A CT angiography (CTA) was performed to rule out any intracranial vascular malformation. A DAVF was noticed at the transverse sinus with dilated cortical venous drainage (Fig. b). So, a digital subtraction angiography (DSA) of the external carotid artery and DAVF embolization was planned.\nNo anomaly was noticed during selective angiography of the internal carotid and vertebral arteries and the left external carotid artery. Selective angiography of the right external carotid artery showed that the DAVF was located at the transverse sinus and fed by posterior branch of the middle meningeal artery (MMA), the occipital artery, and the posterior meningeal artery and drained to the occipital cortical veins with venous ectasia (Fig. a-b). The DAVF was classified as type IV according to the Cognard classification. The embolization was performed via the MMA. The Headway duo catheter was used and accessed to the DAVF, and Onyx was injected until the shunt disappeared (Fig. c-d). The patient experienced an uneventful recovery. His CSDH gradually resolved in 1 month (Fig. ). No neurologic deficit was noticed.\nA PubMed search of published studies written in English and Chinese was conducted on June 30th, 2017. The following key words were used in relevant combinations: dural arteriovenous fistula, dural arteriovenous malformation, subdural hematoma, subdural haematoma, subdural hemorrhage, and subdural haemorrhage. The reference lists of the identified articles were also manually searched for additional studies. Studies of which full text could not be obtained or those without sufficient individualized description of the isolated SDH cases mixed in larger case series were excluded.\nFinally, 13 articles containing 14 patients were identified [–]. In all 15 patients (9 females, 60%) including 1 case in our institution were included for the final interpretation (Table ). The inflicted patients were aged from 27 to 82 years (55.5 ± 8.6).Of note, 12 (80%) of the 15 patients were aged between 40 and 60 years of age, and 8 (53.3%) patients were between 50 and 60 years. Sides of the DAVF or SDH were obtained in 13 patients with 9 (69.2%) located at the left side and 4 at the right side. The intracranial locations of DAVF were anterior fossa (2), middle fossa (2), frontal region (2), parietal region (3), temporal region (2), and occipital region (2). The types of SDH were CSDH (7/15), acute SDH (ASDH) (7/15), and undefined SDH (1/15). Of the 12 patients feeding artery could be identified, MMA was the commonest feeding artery (8/12, 66.7%). Multiple feeding arteries were identified in 3 (25%) patients. The causes of DAVF were only defined in 3 patients (2 iatrogenic and 1 traumatic), with the rest undefined or not mentioned. Cognard classifications (Table ) of the DAVF were reported or deduced from the reports in 12 patients, with type I, type III, and type IV in 7, 2, and 3 patients respectively. The treatment strategies included hematoma evacuation (2/15), CSDH drainage and DAVF embolization (5/15), craniotomy and DAVF resection (3/15), DAVF embolization and hematoma evacuation (1/15), DAVF embolization (2/15), and not applicable or not mentioned (2/15). Of the 12 patients with direct description of outcome, 7 (58.3%) patients were neurological intact, 3 (25%) patients with neurological deficits, and 2 (16.7%) died.

A 68-year-old woman with polycythemia vera experienced a global, nonpositional headache for one day. She subsequently became comatose. On emergent evaluation she exhibited decorticate posturing. Her Glasgow coma score was 6. There was no preceding history of trauma, infection, or dehydration. She was not on anticoagulants or antiplatelet agents. Her polycythemia vera had been managed with therapeutic phlebotomy and hydroxyurea (500 mg daily). She had no prior history of thromboembolic events. Noncontrasted head CT showed extensive left 20 mm acute SDH with 16 mm of midline shift []. She underwent emergent craniotomy and hematoma evacuation. On careful inspection of the exposed brain, a prominent and engorged cortical vein observed. No other vascular abnormalities or potential bleeding sources were identified. CT venography and MR venography detected partial superior sagittal sinus thrombosis, which leads to the empty delta sign (the intraluminal thrombus prevents central filling of the sinus; ). She was managed conservatively with hydroxyurea, hydration, and aspirin. Laboratory analyses were notable for normal coagulation panel, normal platelet function assays, hematocrit of 45.9, negative thrombophilia evaluation (protein S, protein C, antithrombin III, anticardiolipin antibody, homocysteine, lupus anticoagulant, beta-2 glycoprotein antibodies, Factor V Leiden mutation, prothrombin gene mutation). Analysis of DNA extracted from her blood revealed the presence of the V617F mutation within the JAK2 gene. Her 3-month outcome was poor (modified Rankin score 4).

Write a detailed clinical case vignette based on the following key phrases: Subdural Hematoma, Cerebral Venous Thrombosis, Dural Arteriovenous Fistula

A 45-year-old man was admitted for a progressively worsening headache over 2 weeks. He denied history of recent head trauma or anticoagulation and antiplatelet medication. General and neurologic examinations were not remarkable on admission. Routine laboratory investigations including coagulation profiles and platelet function were within normal limits. Head computed tomography (CT) on admission revealed an isodense CSDH on the right hemisphere with mild midline shift (Fig. a). A CT angiography (CTA) was performed to rule out any intracranial vascular malformation. A DAVF was noticed at the transverse sinus with dilated cortical venous drainage (Fig. b). So, a digital subtraction angiography (DSA) of the external carotid artery and DAVF embolization was planned.\nNo anomaly was noticed during selective angiography of the internal carotid and vertebral arteries and the left external carotid artery. Selective angiography of the right external carotid artery showed that the DAVF was located at the transverse sinus and fed by posterior branch of the middle meningeal artery (MMA), the occipital artery, and the posterior meningeal artery and drained to the occipital cortical veins with venous ectasia (Fig. a-b). The DAVF was classified as type IV according to the Cognard classification. The embolization was performed via the MMA. The Headway duo catheter was used and accessed to the DAVF, and Onyx was injected until the shunt disappeared (Fig. c-d). The patient experienced an uneventful recovery. His CSDH gradually resolved in 1 month (Fig. ). No neurologic deficit was noticed.\nA PubMed search of published studies written in English and Chinese was conducted on June 30th, 2017. The following key words were used in relevant combinations: dural arteriovenous fistula, dural arteriovenous malformation, subdural hematoma, subdural haematoma, subdural hemorrhage, and subdural haemorrhage. The reference lists of the identified articles were also manually searched for additional studies. Studies of which full text could not be obtained or those without sufficient individualized description of the isolated SDH cases mixed in larger case series were excluded.\nFinally, 13 articles containing 14 patients were identified [–]. In all 15 patients (9 females, 60%) including 1 case in our institution were included for the final interpretation (Table ). The inflicted patients were aged from 27 to 82 years (55.5 ± 8.6).Of note, 12 (80%) of the 15 patients were aged between 40 and 60 years of age, and 8 (53.3%) patients were between 50 and 60 years. Sides of the DAVF or SDH were obtained in 13 patients with 9 (69.2%) located at the left side and 4 at the right side. The intracranial locations of DAVF were anterior fossa (2), middle fossa (2), frontal region (2), parietal region (3), temporal region (2), and occipital region (2). The types of SDH were CSDH (7/15), acute SDH (ASDH) (7/15), and undefined SDH (1/15). Of the 12 patients feeding artery could be identified, MMA was the commonest feeding artery (8/12, 66.7%). Multiple feeding arteries were identified in 3 (25%) patients. The causes of DAVF were only defined in 3 patients (2 iatrogenic and 1 traumatic), with the rest undefined or not mentioned. Cognard classifications (Table ) of the DAVF were reported or deduced from the reports in 12 patients, with type I, type III, and type IV in 7, 2, and 3 patients respectively. The treatment strategies included hematoma evacuation (2/15), CSDH drainage and DAVF embolization (5/15), craniotomy and DAVF resection (3/15), DAVF embolization and hematoma evacuation (1/15), DAVF embolization (2/15), and not applicable or not mentioned (2/15). Of the 12 patients with direct description of outcome, 7 (58.3%) patients were neurological intact, 3 (25%) patients with neurological deficits, and 2 (16.7%) died.

A 59-year-old male patient suffered from rapidly progressive and pulsatile headache over the right parietal region characterized as thunderclap and nausea. He had no fever. These symptoms were followed by generalized seizure. Neurological examination showed a normal level of consciousness. On examination, meningism was seen. The rest of the physical examination was unremarkable. CT scan head was normal. MRI revealed right parasagittal high fronto-parietal subarachnoid hemorrhage with mild gyral edema. MRV showed superior sagittal sinus and bilateral transverse sinus thrombosis [Figures and ]. DSA confirmed [Figures and ] the diagnosis of DST without any potential cause of SAH. Coagulation testing, including prothrombin time, activated prothrombin time, anticardiolipin antibody titer, antiphospholipid antibody titer, homocysteine titer, and levels of protein C and S, antithrombin III, and fibrinogen were all within normal limits and done simultaneously with MRI, MR Venography, DSA within one to two days of admission. Subcutaneous LMW heparin therapy was given. The patient's condition stabilized after nine days of treatment. Oral warfarin maintained an INR of 2.0-3.0. Patient's improvement was clinically satisfactory within six weeks, Repeat DSA done after six weeks was normal, except minimal filling defect. Patient was followed up at two-weeks intervals for three months

Write a detailed clinical case vignette based on the following key phrases: Subdural Hematoma, Cerebral Venous Thrombosis, Dural Arteriovenous Fistula

We report a case of a 23-year-old male, known case of Down’s syndrome, who presented to our Emergency Department with a complaint of severe headache for three days. It was accompanied by nausea, vomiting, and confusion. There was no history of trauma, seizures, loss of consciousness, change in vision, or relevant signs of virus infection. He was not on any regular medications. His medical background included surgical closure of ventricular septal defects in his childhood. There was no past medical or family history of coagulopathies.\nOn examination, his Glasgow coma score was 14, with normal vital signs. On neurological examination, the patient was confused, with dense right-sided hemiparesis. Liver function test, prothrombin time, partial thromboplastin time, and international normalized ratio were all within normal range. The brain CT scan revealed left-sided subacute SDH with a 12 mm midline shift and uncal herniation ().\nThe patient underwent emergent left-sided craniotomy and SDH evacuation. The blood evacuated was a mixture of dark stained blood and clots. Post-surgery, the patient’s consciousness level returned to normal, and he regained full power in all limbs. His post-operative CT scan showed optimal evacuation of the left-sided hematoma. There was also a new finding of a small right-sided SDH in the parietal region with no significant mass effect (). The CT scans review showed hyperdense areas in the transverse and sigmoid sinus; this raised suspicion of thrombosis. Magnetic resonance venography (MRV) confirmed the diagnosis of CVST in the right transverse and sigmoid sinuses with loss of flow signal ().\nClinically, the patient made an excellent post-operative recovery. After the diagnosis of CVST, we obtained neurology opinion and considered it risky to commence therapeutic anticoagulation in the early post-operative phase. He was started on a prophylactic dose of low molecular heparin. The patient was discharged home one week after surgery. Subsequently, he was readmitted electively two weeks later and was commenced on Apixaban. He was followed up regularly in outpatients and was asymptomatic.\nThe patient re-presented three months later complaining of a headache and recurrent vomiting, with normal consciousness levels. His repeat brain CT showed recollection of hematoma in the left subdural space (). An updated MRV revealed an interval shrinkage of the thrombus in the right sigmoid venous sinus; however, the reduced flow was seen through the sinus. The medical decision was to stop the anticoagulation, and the patient underwent reopening of the left-sided craniotomy and evacuation of the recurrent SDH. He recovered well after surgery, and we elected not to restart anticoagulation and follow-him clinically.\nThe patient remains clinically well. Interval MRI and MRV scans at six months show complete resolution of the SDH, with residual partial thrombosis of the right sigmoid sinus; however, the sinus is patent, and the venous flow is restored ().

A 40-year-old female presented to an emergency in altered sensorium with right hemiplegia with a history of a severe headache and multiple episodes of vomiting 1 day prior to admission. She was on oral contraceptives for last 2 years. Her Glasgow Coma Scale at admission was E1M3V1 and left pupil was dilated and not reacting to light. Computed tomography (CT) of head revealed venous infarct in left temporo-occipito-parietal region with linear area of hemorrhage within it with large left fronto-temporo-parietal acute subdural hematoma with midline shift of 9 mm toward right side with subfalcine herniation with descending transtentorial herniation with sub-arachnoid hemorrhage in the left parietal and occipital sulci with diffuse cerebral edema [].\nCT venography revealed thrombosis in superior sagittal sinus extending to adjacent cortical veins []. She was immediately taken for surgery, and a left fronto-temporo-parietal decompressive craniectomy was performed with the evacuation of acute subdural hematoma and lax duroplasty. However, she continued to deteriorate in the postoperative period and died on the first postoperative day.

Write a detailed clinical case vignette based on the following key phrases: Subdural Hematoma, Cerebral Venous Thrombosis, Dural Arteriovenous Fistula

We report a case of a 23-year-old male, known case of Down’s syndrome, who presented to our Emergency Department with a complaint of severe headache for three days. It was accompanied by nausea, vomiting, and confusion. There was no history of trauma, seizures, loss of consciousness, change in vision, or relevant signs of virus infection. He was not on any regular medications. His medical background included surgical closure of ventricular septal defects in his childhood. There was no past medical or family history of coagulopathies.\nOn examination, his Glasgow coma score was 14, with normal vital signs. On neurological examination, the patient was confused, with dense right-sided hemiparesis. Liver function test, prothrombin time, partial thromboplastin time, and international normalized ratio were all within normal range. The brain CT scan revealed left-sided subacute SDH with a 12 mm midline shift and uncal herniation ().\nThe patient underwent emergent left-sided craniotomy and SDH evacuation. The blood evacuated was a mixture of dark stained blood and clots. Post-surgery, the patient’s consciousness level returned to normal, and he regained full power in all limbs. His post-operative CT scan showed optimal evacuation of the left-sided hematoma. There was also a new finding of a small right-sided SDH in the parietal region with no significant mass effect (). The CT scans review showed hyperdense areas in the transverse and sigmoid sinus; this raised suspicion of thrombosis. Magnetic resonance venography (MRV) confirmed the diagnosis of CVST in the right transverse and sigmoid sinuses with loss of flow signal ().\nClinically, the patient made an excellent post-operative recovery. After the diagnosis of CVST, we obtained neurology opinion and considered it risky to commence therapeutic anticoagulation in the early post-operative phase. He was started on a prophylactic dose of low molecular heparin. The patient was discharged home one week after surgery. Subsequently, he was readmitted electively two weeks later and was commenced on Apixaban. He was followed up regularly in outpatients and was asymptomatic.\nThe patient re-presented three months later complaining of a headache and recurrent vomiting, with normal consciousness levels. His repeat brain CT showed recollection of hematoma in the left subdural space (). An updated MRV revealed an interval shrinkage of the thrombus in the right sigmoid venous sinus; however, the reduced flow was seen through the sinus. The medical decision was to stop the anticoagulation, and the patient underwent reopening of the left-sided craniotomy and evacuation of the recurrent SDH. He recovered well after surgery, and we elected not to restart anticoagulation and follow-him clinically.\nThe patient remains clinically well. Interval MRI and MRV scans at six months show complete resolution of the SDH, with residual partial thrombosis of the right sigmoid sinus; however, the sinus is patent, and the venous flow is restored ().

A 25-year-old primigravida with a history of pre-eclampsia was brought to the emergency department with sudden onset of severe headache. The headache started two days after delivery. It was followed by confusion and loss of consciousness over a few hours. On initial evaluation, the patient was confused with a Glasgow Coma Scale (GCS) of 12/15, blood pressure of 130/90 mmHg, pulse rate of 82 beats/min, respiratory rate of 30/min, temperature 98°C, and oxygen saturation of 97 mmHg at room temperature. On physical examination, bilateral equivocal planters were noted with no other significant findings, and bilateral papillary edema on fundoscopy was seen. The rest of the review system was unremarkable. She underwent an urgent MRI with magnetic resonance venography (MRV) of the brain, which showed right transverse sinus thrombosis with an element of SAH (Figure ).\nCoagulation profile, including thrombin time (TT), prothrombin time (PT), partial thromboplastin time (PTT), antithrombin III, fibrinogen, proteins C and S, antiphospholipid antibody titers, and homocysteine levels, were normal. She was started on a half dosage of low molecular weight heparin (LMWH) (60 mg subcutaneously once a day) with regular monitoring of her blood pressure and GCS. Her GCS started improving; therefore, she was continued on a half dose of LMWH for 10 days, and brain MRI was repeated after 10 days, which showed the gradual resolution of SAH (Figure ). The quantity of LMWH was doubled, and warfarin was started after a full dose of LMWH. After improving her GCS and achievement of international normalized ratio (INR) of two to three, she was discharged with the advice of regular INR monitoring and follow-up to the outpatient department. On follow-up at six weeks, MRI with MRV was repeated, which showed thrombosis had resolved, although a mild filling defect was noted. She was kept on anticoagulants for one year, and on further follow-up at six months, she was doing well.

Write a detailed clinical case vignette based on the following key phrases: Subdural Hematoma, Cerebral Venous Thrombosis, Dural Arteriovenous Fistula

We report a case of a 23-year-old male, known case of Down’s syndrome, who presented to our Emergency Department with a complaint of severe headache for three days. It was accompanied by nausea, vomiting, and confusion. There was no history of trauma, seizures, loss of consciousness, change in vision, or relevant signs of virus infection. He was not on any regular medications. His medical background included surgical closure of ventricular septal defects in his childhood. There was no past medical or family history of coagulopathies.\nOn examination, his Glasgow coma score was 14, with normal vital signs. On neurological examination, the patient was confused, with dense right-sided hemiparesis. Liver function test, prothrombin time, partial thromboplastin time, and international normalized ratio were all within normal range. The brain CT scan revealed left-sided subacute SDH with a 12 mm midline shift and uncal herniation ().\nThe patient underwent emergent left-sided craniotomy and SDH evacuation. The blood evacuated was a mixture of dark stained blood and clots. Post-surgery, the patient’s consciousness level returned to normal, and he regained full power in all limbs. His post-operative CT scan showed optimal evacuation of the left-sided hematoma. There was also a new finding of a small right-sided SDH in the parietal region with no significant mass effect (). The CT scans review showed hyperdense areas in the transverse and sigmoid sinus; this raised suspicion of thrombosis. Magnetic resonance venography (MRV) confirmed the diagnosis of CVST in the right transverse and sigmoid sinuses with loss of flow signal ().\nClinically, the patient made an excellent post-operative recovery. After the diagnosis of CVST, we obtained neurology opinion and considered it risky to commence therapeutic anticoagulation in the early post-operative phase. He was started on a prophylactic dose of low molecular heparin. The patient was discharged home one week after surgery. Subsequently, he was readmitted electively two weeks later and was commenced on Apixaban. He was followed up regularly in outpatients and was asymptomatic.\nThe patient re-presented three months later complaining of a headache and recurrent vomiting, with normal consciousness levels. His repeat brain CT showed recollection of hematoma in the left subdural space (). An updated MRV revealed an interval shrinkage of the thrombus in the right sigmoid venous sinus; however, the reduced flow was seen through the sinus. The medical decision was to stop the anticoagulation, and the patient underwent reopening of the left-sided craniotomy and evacuation of the recurrent SDH. He recovered well after surgery, and we elected not to restart anticoagulation and follow-him clinically.\nThe patient remains clinically well. Interval MRI and MRV scans at six months show complete resolution of the SDH, with residual partial thrombosis of the right sigmoid sinus; however, the sinus is patent, and the venous flow is restored ().

This 67-year-old male man has had a progressively worsening pain on the left cranium over 2 weeks that intractable to some analgesics. There was no recent head trauma or other medical disease in his history. On admission, the general physical and neurologic investigations were not remarkable. Routine laboratory evaluations including coagulation profiles and platelet function were within normal limits.\nBrain computed tomography (CT) scans revealed an isodense left-sided CSDH with marked cerebral shifting (). There was no evidence of source of this hemorrhage with temporal predilection on the CT angiogram. On magnetic resonance (MR) image subsequently obtained, the abnormal intensity within the subarachnoid space and the brain parenchyma was not visible. The patency without steno-occlusion in both transverse and sigmoid sinuses was clearly delineated on T2-weighted sequences (). This patient has received a trephination and SDH drainage, after that he was sent home with resolution of headache. Approximately 2 weeks later, however, he developed an excruciating pain in the temporal and parietal regions with recurrence of subdural collection. The site and density of hematoma was similar to the first presentation (). He was immediately returned for subdural irrigation and decompression through the prior burr-holes. The patient's clinical course was not eventful, but he complained of a mild headache again. Follow-up CT scanned just prior to discharge was strikingly for the newly-formed thin hematoma at the operative site (). Another evacuation of this subacute subdural clot was not deemed to be necessary.\nAt this time, an active intervention was sought for this patient who had an intractably recurring CSDH. On the 7th day after the second surgery, angiography was performed to rule out an occult vascular lesion. A flow-guided type microcatheter (Prowler 10™, Cordis Neurovascular, Miami Lakes, FL, USA) was positioned in the main trunk of the MMA for selective angiography. The frontal and parietal branch of the MMA was appeared normally, and the abnormal membrane staining on the affected side was not detected. A left external carotid angiogram disclosed a dural AVF between the petrosquamosal branch of the MMA and the transverse-sigmoid sinus without retrograde cortical venous draining. The AV shunt had no connection to the internal carotid artery and its branches. It was suggested that the bleeding from the draining venous system of the dural AVF led to refractory CSDH. The microcatheter was introduced into the petrosquamosal branch of the MMA, thereafter polyvinyl alcohol particles ranging 150 to 250 µm were distally injected (). After trans-arterial obliteration of the feeder and fistula, the AV shunt disappeared. The recurrent hematoma of this patient did not increase, and his complaints of headache gradually subsided. The brain CT at one year following the embolization therapy revealed complete regression of the subdural hematomas ().

Write a detailed clinical case vignette based on the following key phrases: Subdural Hematoma, Cerebral Venous Thrombosis, Dural Arteriovenous Fistula

We report a case of a 23-year-old male, known case of Down’s syndrome, who presented to our Emergency Department with a complaint of severe headache for three days. It was accompanied by nausea, vomiting, and confusion. There was no history of trauma, seizures, loss of consciousness, change in vision, or relevant signs of virus infection. He was not on any regular medications. His medical background included surgical closure of ventricular septal defects in his childhood. There was no past medical or family history of coagulopathies.\nOn examination, his Glasgow coma score was 14, with normal vital signs. On neurological examination, the patient was confused, with dense right-sided hemiparesis. Liver function test, prothrombin time, partial thromboplastin time, and international normalized ratio were all within normal range. The brain CT scan revealed left-sided subacute SDH with a 12 mm midline shift and uncal herniation ().\nThe patient underwent emergent left-sided craniotomy and SDH evacuation. The blood evacuated was a mixture of dark stained blood and clots. Post-surgery, the patient’s consciousness level returned to normal, and he regained full power in all limbs. His post-operative CT scan showed optimal evacuation of the left-sided hematoma. There was also a new finding of a small right-sided SDH in the parietal region with no significant mass effect (). The CT scans review showed hyperdense areas in the transverse and sigmoid sinus; this raised suspicion of thrombosis. Magnetic resonance venography (MRV) confirmed the diagnosis of CVST in the right transverse and sigmoid sinuses with loss of flow signal ().\nClinically, the patient made an excellent post-operative recovery. After the diagnosis of CVST, we obtained neurology opinion and considered it risky to commence therapeutic anticoagulation in the early post-operative phase. He was started on a prophylactic dose of low molecular heparin. The patient was discharged home one week after surgery. Subsequently, he was readmitted electively two weeks later and was commenced on Apixaban. He was followed up regularly in outpatients and was asymptomatic.\nThe patient re-presented three months later complaining of a headache and recurrent vomiting, with normal consciousness levels. His repeat brain CT showed recollection of hematoma in the left subdural space (). An updated MRV revealed an interval shrinkage of the thrombus in the right sigmoid venous sinus; however, the reduced flow was seen through the sinus. The medical decision was to stop the anticoagulation, and the patient underwent reopening of the left-sided craniotomy and evacuation of the recurrent SDH. He recovered well after surgery, and we elected not to restart anticoagulation and follow-him clinically.\nThe patient remains clinically well. Interval MRI and MRV scans at six months show complete resolution of the SDH, with residual partial thrombosis of the right sigmoid sinus; however, the sinus is patent, and the venous flow is restored ().

A 66-year-old male with a recent syncope-related fall and closed head injury presented with progressively worsening gait instability, dizziness, and headaches. The fall occurred 1 week before presentation. On examination, no focal neurologic deficits were found. Noncontrast head CT demonstrated a 7 mm right convexity mixed density subdural hematoma [ and ]. Given his significant headaches and progressive functional decline, MMA embolization was performed as primary treatment. Intraprocedural digital subtraction angiogram revealed a right parietal Cognard Grade I DAVF [ and ]. Given the absence of cortical venous reflux and benign natural history of the fistula, the remainder of the procedure did not deviate from routine MMA embolization. The right temporal and right frontoparietal branches of the MMA were embolized with n-BCA glue with indirect penetration of liquid embolic into the fistulous point. Following embolization, there was no further opacification of the fistula. The patient experienced no procedure-related complication and was discharged the subsequent day. At 1-month follow-up, there was complete resolution of his presenting symptoms and surveillance CT demonstrated no residual SDH.

Write a detailed clinical case vignette based on the following key phrases: Subdural Hematoma, Cerebral Venous Thrombosis, Dural Arteriovenous Fistula

We report a case of a 23-year-old male, known case of Down’s syndrome, who presented to our Emergency Department with a complaint of severe headache for three days. It was accompanied by nausea, vomiting, and confusion. There was no history of trauma, seizures, loss of consciousness, change in vision, or relevant signs of virus infection. He was not on any regular medications. His medical background included surgical closure of ventricular septal defects in his childhood. There was no past medical or family history of coagulopathies.\nOn examination, his Glasgow coma score was 14, with normal vital signs. On neurological examination, the patient was confused, with dense right-sided hemiparesis. Liver function test, prothrombin time, partial thromboplastin time, and international normalized ratio were all within normal range. The brain CT scan revealed left-sided subacute SDH with a 12 mm midline shift and uncal herniation ().\nThe patient underwent emergent left-sided craniotomy and SDH evacuation. The blood evacuated was a mixture of dark stained blood and clots. Post-surgery, the patient’s consciousness level returned to normal, and he regained full power in all limbs. His post-operative CT scan showed optimal evacuation of the left-sided hematoma. There was also a new finding of a small right-sided SDH in the parietal region with no significant mass effect (). The CT scans review showed hyperdense areas in the transverse and sigmoid sinus; this raised suspicion of thrombosis. Magnetic resonance venography (MRV) confirmed the diagnosis of CVST in the right transverse and sigmoid sinuses with loss of flow signal ().\nClinically, the patient made an excellent post-operative recovery. After the diagnosis of CVST, we obtained neurology opinion and considered it risky to commence therapeutic anticoagulation in the early post-operative phase. He was started on a prophylactic dose of low molecular heparin. The patient was discharged home one week after surgery. Subsequently, he was readmitted electively two weeks later and was commenced on Apixaban. He was followed up regularly in outpatients and was asymptomatic.\nThe patient re-presented three months later complaining of a headache and recurrent vomiting, with normal consciousness levels. His repeat brain CT showed recollection of hematoma in the left subdural space (). An updated MRV revealed an interval shrinkage of the thrombus in the right sigmoid venous sinus; however, the reduced flow was seen through the sinus. The medical decision was to stop the anticoagulation, and the patient underwent reopening of the left-sided craniotomy and evacuation of the recurrent SDH. He recovered well after surgery, and we elected not to restart anticoagulation and follow-him clinically.\nThe patient remains clinically well. Interval MRI and MRV scans at six months show complete resolution of the SDH, with residual partial thrombosis of the right sigmoid sinus; however, the sinus is patent, and the venous flow is restored ().

A 58-year-old right-handed postmenopausal woman presented to the emergency with progressively increasing holocephalic headache for 3 days. She did not have fever, nausea, and vomiting. The headache gradually worsened in severity and on the day of presentation, she developed a generalized tonic clonic seizure. Apart from the history of well-controlled diabetes mellitus, she did not have significant past medical, personal, and family history. She had not received any vaccines in the recent past. On examination, she was ill-looking, but her vital signs were stable. She had Wernicke's aphasia. She did not have disc edema; cranial nerve examination was normal, and she did not have any focal deficits.\nAn urgent CT scan of the head without contrast showed left temporal hematoma with surrounding vasogenic edema (Figure ). Hemorrhagic picture was noted in the insular cistern (Figure ), left fronto-temporal subdural space (Figure ), the perimesencephalic, ambient and suprasellar cisterns (Figures and ), and the sulci of the left temporo-parietal lobes (Figures and ). There was a subtle dense clot sign in the left transverse sinus (Figure ). She was diagnosed as having left transverse sinus thrombosis leading to left temporal hematoma, SAH and SDH. She was treated with low molecular weight heparin, levetiracetam, and 3% hypertonic saline. The magnetic resonance venography (MRV) done the following day confirmed the presence of left transverse sinus thrombosis (Figure ). CT angiography of the brain did not reveal any vascular malformations. Her complete blood counts, coagulation profiles, routine blood chemistry, and C-reactive protein were within normal limits. Antinuclear antibody and SARS-CoV-2 RNA polymerase chain reaction tests were negative. She underwent CT scan of neck, chest, abdomen and pelvis, mammogram, stool occult blood, carcinoembryonic antigen, CA-125, and Ca 19–9 tests, all of which were non-contributory to any occult malignancy. Thrombophilia screening was not done at this acute stage. We decided to get those done after the completion of anticoagulant treatment. She showed good clinical improvement over the course of the next few days. A repeat CT scan of the head done on day seven, revealed decreasing edema and stable hematoma volume with no new bleeding. The cause of her CVST was deemed undermined at this stage and she was discharged home on dabigatran 150 mg twice daily, as she could not get PT/INR done reliably due to the current lockdown imposed by the government. She has been doing well on follow up.

Write a detailed clinical case vignette based on the following key phrases: Subdural Hematoma, Cerebral Venous Thrombosis, Dural Arteriovenous Fistula

We report a case of a 23-year-old male, known case of Down’s syndrome, who presented to our Emergency Department with a complaint of severe headache for three days. It was accompanied by nausea, vomiting, and confusion. There was no history of trauma, seizures, loss of consciousness, change in vision, or relevant signs of virus infection. He was not on any regular medications. His medical background included surgical closure of ventricular septal defects in his childhood. There was no past medical or family history of coagulopathies.\nOn examination, his Glasgow coma score was 14, with normal vital signs. On neurological examination, the patient was confused, with dense right-sided hemiparesis. Liver function test, prothrombin time, partial thromboplastin time, and international normalized ratio were all within normal range. The brain CT scan revealed left-sided subacute SDH with a 12 mm midline shift and uncal herniation ().\nThe patient underwent emergent left-sided craniotomy and SDH evacuation. The blood evacuated was a mixture of dark stained blood and clots. Post-surgery, the patient’s consciousness level returned to normal, and he regained full power in all limbs. His post-operative CT scan showed optimal evacuation of the left-sided hematoma. There was also a new finding of a small right-sided SDH in the parietal region with no significant mass effect (). The CT scans review showed hyperdense areas in the transverse and sigmoid sinus; this raised suspicion of thrombosis. Magnetic resonance venography (MRV) confirmed the diagnosis of CVST in the right transverse and sigmoid sinuses with loss of flow signal ().\nClinically, the patient made an excellent post-operative recovery. After the diagnosis of CVST, we obtained neurology opinion and considered it risky to commence therapeutic anticoagulation in the early post-operative phase. He was started on a prophylactic dose of low molecular heparin. The patient was discharged home one week after surgery. Subsequently, he was readmitted electively two weeks later and was commenced on Apixaban. He was followed up regularly in outpatients and was asymptomatic.\nThe patient re-presented three months later complaining of a headache and recurrent vomiting, with normal consciousness levels. His repeat brain CT showed recollection of hematoma in the left subdural space (). An updated MRV revealed an interval shrinkage of the thrombus in the right sigmoid venous sinus; however, the reduced flow was seen through the sinus. The medical decision was to stop the anticoagulation, and the patient underwent reopening of the left-sided craniotomy and evacuation of the recurrent SDH. He recovered well after surgery, and we elected not to restart anticoagulation and follow-him clinically.\nThe patient remains clinically well. Interval MRI and MRV scans at six months show complete resolution of the SDH, with residual partial thrombosis of the right sigmoid sinus; however, the sinus is patent, and the venous flow is restored ().

A 77-year-old male with a recent syncope-related fall and closed head injury presented with gradually worsening isolated right upper extremity monoparesis. The fall occurred 1 month before presentation. On examination, the patient demonstrated 4/5 strength in his right upper extremity, with no additional neurologic deficits. Noncontrast head CT demonstrated bilateral mixed density convexity subdural hematomas [22 mm on the left and 14 mm on the right; and ]. The patient underwent a left craniotomy for evacuation of the larger hematoma, in conjunction with bilateral MMA embolization as primary treatment for the right convexity subdural hematoma in addition to limiting potential recurrence along the left convexity. Intraprocedural digital subtraction angiogram revealed two Cognard Grade III DAVFs, one arising from the parietal branch of the right MMA draining into an occipital cortical vein, and the second arising from the temporal branch of the left MMA draining into the vein of Labbe [-]. Given the presence of cortical venous reflux and associated risk of future intracranial hemorrhage, treatment of the fistulae was indicated. This was approached in two staged procedures. Following an uncomplicated left MMA embolization (frontoparietal branch), the incidental findings were discussed with the patient and he underwent a second stage embolization for the DAVF on a later date. During the second stage, a more prolonged infusion of liquid embolic was employed to ensure penetration into the recipient cortical venous outflow, resulting in nonopacification of the aforementioned fistulae. The postoperative course was complicated by seizures which resolved with uptitration in antiepileptic medications. At 6-month follow-up, there was complete resolution of the patient’s presenting symptoms and surveillance CT demonstrated no residual SDH.

Write a detailed clinical case vignette based on the following key phrases: Subdural Hematoma, Cerebral Venous Thrombosis, Dural Arteriovenous Fistula

We report a case of a 23-year-old male, known case of Down’s syndrome, who presented to our Emergency Department with a complaint of severe headache for three days. It was accompanied by nausea, vomiting, and confusion. There was no history of trauma, seizures, loss of consciousness, change in vision, or relevant signs of virus infection. He was not on any regular medications. His medical background included surgical closure of ventricular septal defects in his childhood. There was no past medical or family history of coagulopathies.\nOn examination, his Glasgow coma score was 14, with normal vital signs. On neurological examination, the patient was confused, with dense right-sided hemiparesis. Liver function test, prothrombin time, partial thromboplastin time, and international normalized ratio were all within normal range. The brain CT scan revealed left-sided subacute SDH with a 12 mm midline shift and uncal herniation ().\nThe patient underwent emergent left-sided craniotomy and SDH evacuation. The blood evacuated was a mixture of dark stained blood and clots. Post-surgery, the patient’s consciousness level returned to normal, and he regained full power in all limbs. His post-operative CT scan showed optimal evacuation of the left-sided hematoma. There was also a new finding of a small right-sided SDH in the parietal region with no significant mass effect (). The CT scans review showed hyperdense areas in the transverse and sigmoid sinus; this raised suspicion of thrombosis. Magnetic resonance venography (MRV) confirmed the diagnosis of CVST in the right transverse and sigmoid sinuses with loss of flow signal ().\nClinically, the patient made an excellent post-operative recovery. After the diagnosis of CVST, we obtained neurology opinion and considered it risky to commence therapeutic anticoagulation in the early post-operative phase. He was started on a prophylactic dose of low molecular heparin. The patient was discharged home one week after surgery. Subsequently, he was readmitted electively two weeks later and was commenced on Apixaban. He was followed up regularly in outpatients and was asymptomatic.\nThe patient re-presented three months later complaining of a headache and recurrent vomiting, with normal consciousness levels. His repeat brain CT showed recollection of hematoma in the left subdural space (). An updated MRV revealed an interval shrinkage of the thrombus in the right sigmoid venous sinus; however, the reduced flow was seen through the sinus. The medical decision was to stop the anticoagulation, and the patient underwent reopening of the left-sided craniotomy and evacuation of the recurrent SDH. He recovered well after surgery, and we elected not to restart anticoagulation and follow-him clinically.\nThe patient remains clinically well. Interval MRI and MRV scans at six months show complete resolution of the SDH, with residual partial thrombosis of the right sigmoid sinus; however, the sinus is patent, and the venous flow is restored ().

A 60-year-old male experienced one month of escalating bifrontal headaches refractory to analgesics and antibiotics prescribed for presumed sinusitis. The headaches increased during sneezing, bending over, or bedrest and improved when he was sitting or standing. There was no history of trauma. His prior medical history was notable for hypertension and hyperlipidemia. There was no family history of coagulopathy or thrombophilia. He was married, employed, used 0.5 packs of tobacco (7.5 packs/years), consumed alcohol socially, and did not use any illicit drugs. His vital signs were notable for sinus bradycardia with a heart rate of 39 and elevated BP of 184/86 mmHg. He had no other significant findings on physical examination; detailed neurologic examination was unremarkable. Routine admission laboratory studies were within normal limits. Coagulation studies including platelet function assays were normal.\nNoncontrasted head CT demonstrated a 19 mm left isodense SDH with 10 mm of midline shift []. The collection was more prominent in the frontal region. A CT angiogram was obtained prior to surgery, and no source of bleeding was identified. He underwent a mini-craniotomy; and repeat CT imaging after the procedure [] demonstrated excellent hematoma evacuation and brain reexpansion.\nA scheduled follow up head CT obtained on postoperative day 27 was notable for recurrent SDH with a frontal predilection \n[]. The appearance and location were similar to the initial presentation. He was readmitted to the hospital and underwent SDH drainage via burr hole. On subsequent imaging with MRI, MR angiography, and MR venography, a filling defect was visible in the distal left transverse sinus and no flow was observed in the distal left sigmoid sinus or internal jugular vein. These findings were confirmed on CT venography.\nPatient underwent cerebral angiography on postoperative day 7 after SDH evacuation []. Left carotid injection was notable for a prominent left vein of Labbe with delayed wash-out, a filling defect in the left transverse sinus, and retrograde flow in the left transverse sinus with subsequent drainage into the right transverse sinus. Transvenous catheterization confirmed retrograde drainage of the left transverse sinus and venous stasis in the left vein of Labbe. Manometric readings in the left sigmoid sinus and both transverse sinuses were elevated (18-25 mmHg range). Thrombectomy with the Penumbra device and venoplasty with 7 × 20 mm balloon were performed; 10 mg of systemic abciximab was administered. Follow up venography demonstrated improved flow in the left vein of Labbe, restored normal direction of flow in the sinuses with normalized pressure (11 mmHg) in the left transverse sinus. Daily aspirin (325 mg) was initiated on the day of this intervention; patient was discharged home without neurologic deficits. A follow-up CT venogram at 6 weeks demonstrated patent venous sinuses and no recurrence of his SDH. His 3 month clinical outcome was excellent (modified Rankin score 0).

Write a detailed clinical case vignette based on the following key phrases: Subdural Hematoma, Cerebral Venous Thrombosis, Dural Arteriovenous Fistula

We report a case of a 23-year-old male, known case of Down’s syndrome, who presented to our Emergency Department with a complaint of severe headache for three days. It was accompanied by nausea, vomiting, and confusion. There was no history of trauma, seizures, loss of consciousness, change in vision, or relevant signs of virus infection. He was not on any regular medications. His medical background included surgical closure of ventricular septal defects in his childhood. There was no past medical or family history of coagulopathies.\nOn examination, his Glasgow coma score was 14, with normal vital signs. On neurological examination, the patient was confused, with dense right-sided hemiparesis. Liver function test, prothrombin time, partial thromboplastin time, and international normalized ratio were all within normal range. The brain CT scan revealed left-sided subacute SDH with a 12 mm midline shift and uncal herniation ().\nThe patient underwent emergent left-sided craniotomy and SDH evacuation. The blood evacuated was a mixture of dark stained blood and clots. Post-surgery, the patient’s consciousness level returned to normal, and he regained full power in all limbs. His post-operative CT scan showed optimal evacuation of the left-sided hematoma. There was also a new finding of a small right-sided SDH in the parietal region with no significant mass effect (). The CT scans review showed hyperdense areas in the transverse and sigmoid sinus; this raised suspicion of thrombosis. Magnetic resonance venography (MRV) confirmed the diagnosis of CVST in the right transverse and sigmoid sinuses with loss of flow signal ().\nClinically, the patient made an excellent post-operative recovery. After the diagnosis of CVST, we obtained neurology opinion and considered it risky to commence therapeutic anticoagulation in the early post-operative phase. He was started on a prophylactic dose of low molecular heparin. The patient was discharged home one week after surgery. Subsequently, he was readmitted electively two weeks later and was commenced on Apixaban. He was followed up regularly in outpatients and was asymptomatic.\nThe patient re-presented three months later complaining of a headache and recurrent vomiting, with normal consciousness levels. His repeat brain CT showed recollection of hematoma in the left subdural space (). An updated MRV revealed an interval shrinkage of the thrombus in the right sigmoid venous sinus; however, the reduced flow was seen through the sinus. The medical decision was to stop the anticoagulation, and the patient underwent reopening of the left-sided craniotomy and evacuation of the recurrent SDH. He recovered well after surgery, and we elected not to restart anticoagulation and follow-him clinically.\nThe patient remains clinically well. Interval MRI and MRV scans at six months show complete resolution of the SDH, with residual partial thrombosis of the right sigmoid sinus; however, the sinus is patent, and the venous flow is restored ().

A 59-year-old male with a recent fall and closed head injury presented with progressively worsening headaches. The fall occurred 9 days before presentation. On examination, no neurologic deficits were found. Noncontrast head CT demonstrated a 5 mm left convexity CSDH []. He underwent burr hole evacuation and was discharged on the subsequent day. He presented again on postoperative day 6 with recurrence of his headaches. Noncontrast head CT demonstrated recurrence of the left convexity subdural hematoma []. He subsequently underwent a left craniotomy for evacuation. He was discharged on postoperative day 2 with no postprocedural complications. At 1-month follow-up, he continued to complain of severe headaches. Surveillance CT demonstrated a new 27 mm right convexity mixed density subdural hematoma [ and ]. He subsequently underwent right MMA embolization as primary treatment. Intraprocedural digital subtraction angiogram revealed a Cognard Grade III cribriform plate DAVF supplied by the right ophthalmic artery draining into a right frontal cortical vein [ and ]. The right MMA temporoparietal and frontal branches were embolized with n-BCA glue. Follow-up was arranged to treat the DAVF at a later date and he was discharged the following day. The patient was subsequently lost to follow-up, but presented to the emergency department 4 months later with diplopia and a right abducens nerve palsy. Noncontrast head CT demonstrated significant reduction in size of the previously embolized right convexity subdural hematoma. He was admitted and underwent attempted endovascular treatment of the DAVF. Catheterization of the arterial and venous sides of the fistula achieved suboptimal positioning for liquid embolic embolization and so he underwent a right craniotomy for surgical ligation of the fistula. The patient experienced no postprocedural complications. At 2-week follow-up, there was complete resolution of his presenting symptoms and surveillance CT demonstrated no residual SDH.

Write a detailed clinical case vignette based on the following key phrases: Subdural Hematoma, Cerebral Venous Thrombosis, Dural Arteriovenous Fistula

We report a case of a 23-year-old male, known case of Down’s syndrome, who presented to our Emergency Department with a complaint of severe headache for three days. It was accompanied by nausea, vomiting, and confusion. There was no history of trauma, seizures, loss of consciousness, change in vision, or relevant signs of virus infection. He was not on any regular medications. His medical background included surgical closure of ventricular septal defects in his childhood. There was no past medical or family history of coagulopathies.\nOn examination, his Glasgow coma score was 14, with normal vital signs. On neurological examination, the patient was confused, with dense right-sided hemiparesis. Liver function test, prothrombin time, partial thromboplastin time, and international normalized ratio were all within normal range. The brain CT scan revealed left-sided subacute SDH with a 12 mm midline shift and uncal herniation ().\nThe patient underwent emergent left-sided craniotomy and SDH evacuation. The blood evacuated was a mixture of dark stained blood and clots. Post-surgery, the patient’s consciousness level returned to normal, and he regained full power in all limbs. His post-operative CT scan showed optimal evacuation of the left-sided hematoma. There was also a new finding of a small right-sided SDH in the parietal region with no significant mass effect (). The CT scans review showed hyperdense areas in the transverse and sigmoid sinus; this raised suspicion of thrombosis. Magnetic resonance venography (MRV) confirmed the diagnosis of CVST in the right transverse and sigmoid sinuses with loss of flow signal ().\nClinically, the patient made an excellent post-operative recovery. After the diagnosis of CVST, we obtained neurology opinion and considered it risky to commence therapeutic anticoagulation in the early post-operative phase. He was started on a prophylactic dose of low molecular heparin. The patient was discharged home one week after surgery. Subsequently, he was readmitted electively two weeks later and was commenced on Apixaban. He was followed up regularly in outpatients and was asymptomatic.\nThe patient re-presented three months later complaining of a headache and recurrent vomiting, with normal consciousness levels. His repeat brain CT showed recollection of hematoma in the left subdural space (). An updated MRV revealed an interval shrinkage of the thrombus in the right sigmoid venous sinus; however, the reduced flow was seen through the sinus. The medical decision was to stop the anticoagulation, and the patient underwent reopening of the left-sided craniotomy and evacuation of the recurrent SDH. He recovered well after surgery, and we elected not to restart anticoagulation and follow-him clinically.\nThe patient remains clinically well. Interval MRI and MRV scans at six months show complete resolution of the SDH, with residual partial thrombosis of the right sigmoid sinus; however, the sinus is patent, and the venous flow is restored ().

A 68-year-old woman with polycythemia vera experienced a global, nonpositional headache for one day. She subsequently became comatose. On emergent evaluation she exhibited decorticate posturing. Her Glasgow coma score was 6. There was no preceding history of trauma, infection, or dehydration. She was not on anticoagulants or antiplatelet agents. Her polycythemia vera had been managed with therapeutic phlebotomy and hydroxyurea (500 mg daily). She had no prior history of thromboembolic events. Noncontrasted head CT showed extensive left 20 mm acute SDH with 16 mm of midline shift []. She underwent emergent craniotomy and hematoma evacuation. On careful inspection of the exposed brain, a prominent and engorged cortical vein observed. No other vascular abnormalities or potential bleeding sources were identified. CT venography and MR venography detected partial superior sagittal sinus thrombosis, which leads to the empty delta sign (the intraluminal thrombus prevents central filling of the sinus; ). She was managed conservatively with hydroxyurea, hydration, and aspirin. Laboratory analyses were notable for normal coagulation panel, normal platelet function assays, hematocrit of 45.9, negative thrombophilia evaluation (protein S, protein C, antithrombin III, anticardiolipin antibody, homocysteine, lupus anticoagulant, beta-2 glycoprotein antibodies, Factor V Leiden mutation, prothrombin gene mutation). Analysis of DNA extracted from her blood revealed the presence of the V617F mutation within the JAK2 gene. Her 3-month outcome was poor (modified Rankin score 4).

Write a detailed clinical case vignette based on the following key phrases: Subdural Hematoma, Cerebral Venous Thrombosis, Dural Arteriovenous Fistula

We report a case of a 23-year-old male, known case of Down’s syndrome, who presented to our Emergency Department with a complaint of severe headache for three days. It was accompanied by nausea, vomiting, and confusion. There was no history of trauma, seizures, loss of consciousness, change in vision, or relevant signs of virus infection. He was not on any regular medications. His medical background included surgical closure of ventricular septal defects in his childhood. There was no past medical or family history of coagulopathies.\nOn examination, his Glasgow coma score was 14, with normal vital signs. On neurological examination, the patient was confused, with dense right-sided hemiparesis. Liver function test, prothrombin time, partial thromboplastin time, and international normalized ratio were all within normal range. The brain CT scan revealed left-sided subacute SDH with a 12 mm midline shift and uncal herniation ().\nThe patient underwent emergent left-sided craniotomy and SDH evacuation. The blood evacuated was a mixture of dark stained blood and clots. Post-surgery, the patient’s consciousness level returned to normal, and he regained full power in all limbs. His post-operative CT scan showed optimal evacuation of the left-sided hematoma. There was also a new finding of a small right-sided SDH in the parietal region with no significant mass effect (). The CT scans review showed hyperdense areas in the transverse and sigmoid sinus; this raised suspicion of thrombosis. Magnetic resonance venography (MRV) confirmed the diagnosis of CVST in the right transverse and sigmoid sinuses with loss of flow signal ().\nClinically, the patient made an excellent post-operative recovery. After the diagnosis of CVST, we obtained neurology opinion and considered it risky to commence therapeutic anticoagulation in the early post-operative phase. He was started on a prophylactic dose of low molecular heparin. The patient was discharged home one week after surgery. Subsequently, he was readmitted electively two weeks later and was commenced on Apixaban. He was followed up regularly in outpatients and was asymptomatic.\nThe patient re-presented three months later complaining of a headache and recurrent vomiting, with normal consciousness levels. His repeat brain CT showed recollection of hematoma in the left subdural space (). An updated MRV revealed an interval shrinkage of the thrombus in the right sigmoid venous sinus; however, the reduced flow was seen through the sinus. The medical decision was to stop the anticoagulation, and the patient underwent reopening of the left-sided craniotomy and evacuation of the recurrent SDH. He recovered well after surgery, and we elected not to restart anticoagulation and follow-him clinically.\nThe patient remains clinically well. Interval MRI and MRV scans at six months show complete resolution of the SDH, with residual partial thrombosis of the right sigmoid sinus; however, the sinus is patent, and the venous flow is restored ().

A 59-year-old male patient suffered from rapidly progressive and pulsatile headache over the right parietal region characterized as thunderclap and nausea. He had no fever. These symptoms were followed by generalized seizure. Neurological examination showed a normal level of consciousness. On examination, meningism was seen. The rest of the physical examination was unremarkable. CT scan head was normal. MRI revealed right parasagittal high fronto-parietal subarachnoid hemorrhage with mild gyral edema. MRV showed superior sagittal sinus and bilateral transverse sinus thrombosis [Figures and ]. DSA confirmed [Figures and ] the diagnosis of DST without any potential cause of SAH. Coagulation testing, including prothrombin time, activated prothrombin time, anticardiolipin antibody titer, antiphospholipid antibody titer, homocysteine titer, and levels of protein C and S, antithrombin III, and fibrinogen were all within normal limits and done simultaneously with MRI, MR Venography, DSA within one to two days of admission. Subcutaneous LMW heparin therapy was given. The patient's condition stabilized after nine days of treatment. Oral warfarin maintained an INR of 2.0-3.0. Patient's improvement was clinically satisfactory within six weeks, Repeat DSA done after six weeks was normal, except minimal filling defect. Patient was followed up at two-weeks intervals for three months

Write a detailed clinical case vignette based on the following key phrases: Subdural Hematoma, Cerebral Venous Thrombosis, Dural Arteriovenous Fistula

A 25-year-old primigravida with a history of pre-eclampsia was brought to the emergency department with sudden onset of severe headache. The headache started two days after delivery. It was followed by confusion and loss of consciousness over a few hours. On initial evaluation, the patient was confused with a Glasgow Coma Scale (GCS) of 12/15, blood pressure of 130/90 mmHg, pulse rate of 82 beats/min, respiratory rate of 30/min, temperature 98°C, and oxygen saturation of 97 mmHg at room temperature. On physical examination, bilateral equivocal planters were noted with no other significant findings, and bilateral papillary edema on fundoscopy was seen. The rest of the review system was unremarkable. She underwent an urgent MRI with magnetic resonance venography (MRV) of the brain, which showed right transverse sinus thrombosis with an element of SAH (Figure ).\nCoagulation profile, including thrombin time (TT), prothrombin time (PT), partial thromboplastin time (PTT), antithrombin III, fibrinogen, proteins C and S, antiphospholipid antibody titers, and homocysteine levels, were normal. She was started on a half dosage of low molecular weight heparin (LMWH) (60 mg subcutaneously once a day) with regular monitoring of her blood pressure and GCS. Her GCS started improving; therefore, she was continued on a half dose of LMWH for 10 days, and brain MRI was repeated after 10 days, which showed the gradual resolution of SAH (Figure ). The quantity of LMWH was doubled, and warfarin was started after a full dose of LMWH. After improving her GCS and achievement of international normalized ratio (INR) of two to three, she was discharged with the advice of regular INR monitoring and follow-up to the outpatient department. On follow-up at six weeks, MRI with MRV was repeated, which showed thrombosis had resolved, although a mild filling defect was noted. She was kept on anticoagulants for one year, and on further follow-up at six months, she was doing well.

A 40-year-old female presented to an emergency in altered sensorium with right hemiplegia with a history of a severe headache and multiple episodes of vomiting 1 day prior to admission. She was on oral contraceptives for last 2 years. Her Glasgow Coma Scale at admission was E1M3V1 and left pupil was dilated and not reacting to light. Computed tomography (CT) of head revealed venous infarct in left temporo-occipito-parietal region with linear area of hemorrhage within it with large left fronto-temporo-parietal acute subdural hematoma with midline shift of 9 mm toward right side with subfalcine herniation with descending transtentorial herniation with sub-arachnoid hemorrhage in the left parietal and occipital sulci with diffuse cerebral edema [].\nCT venography revealed thrombosis in superior sagittal sinus extending to adjacent cortical veins []. She was immediately taken for surgery, and a left fronto-temporo-parietal decompressive craniectomy was performed with the evacuation of acute subdural hematoma and lax duroplasty. However, she continued to deteriorate in the postoperative period and died on the first postoperative day.

Write a detailed clinical case vignette based on the following key phrases: Subdural Hematoma, Cerebral Venous Thrombosis, Dural Arteriovenous Fistula

This 67-year-old male man has had a progressively worsening pain on the left cranium over 2 weeks that intractable to some analgesics. There was no recent head trauma or other medical disease in his history. On admission, the general physical and neurologic investigations were not remarkable. Routine laboratory evaluations including coagulation profiles and platelet function were within normal limits.\nBrain computed tomography (CT) scans revealed an isodense left-sided CSDH with marked cerebral shifting (). There was no evidence of source of this hemorrhage with temporal predilection on the CT angiogram. On magnetic resonance (MR) image subsequently obtained, the abnormal intensity within the subarachnoid space and the brain parenchyma was not visible. The patency without steno-occlusion in both transverse and sigmoid sinuses was clearly delineated on T2-weighted sequences (). This patient has received a trephination and SDH drainage, after that he was sent home with resolution of headache. Approximately 2 weeks later, however, he developed an excruciating pain in the temporal and parietal regions with recurrence of subdural collection. The site and density of hematoma was similar to the first presentation (). He was immediately returned for subdural irrigation and decompression through the prior burr-holes. The patient's clinical course was not eventful, but he complained of a mild headache again. Follow-up CT scanned just prior to discharge was strikingly for the newly-formed thin hematoma at the operative site (). Another evacuation of this subacute subdural clot was not deemed to be necessary.\nAt this time, an active intervention was sought for this patient who had an intractably recurring CSDH. On the 7th day after the second surgery, angiography was performed to rule out an occult vascular lesion. A flow-guided type microcatheter (Prowler 10™, Cordis Neurovascular, Miami Lakes, FL, USA) was positioned in the main trunk of the MMA for selective angiography. The frontal and parietal branch of the MMA was appeared normally, and the abnormal membrane staining on the affected side was not detected. A left external carotid angiogram disclosed a dural AVF between the petrosquamosal branch of the MMA and the transverse-sigmoid sinus without retrograde cortical venous draining. The AV shunt had no connection to the internal carotid artery and its branches. It was suggested that the bleeding from the draining venous system of the dural AVF led to refractory CSDH. The microcatheter was introduced into the petrosquamosal branch of the MMA, thereafter polyvinyl alcohol particles ranging 150 to 250 µm were distally injected (). After trans-arterial obliteration of the feeder and fistula, the AV shunt disappeared. The recurrent hematoma of this patient did not increase, and his complaints of headache gradually subsided. The brain CT at one year following the embolization therapy revealed complete regression of the subdural hematomas ().

A 40-year-old female presented to an emergency in altered sensorium with right hemiplegia with a history of a severe headache and multiple episodes of vomiting 1 day prior to admission. She was on oral contraceptives for last 2 years. Her Glasgow Coma Scale at admission was E1M3V1 and left pupil was dilated and not reacting to light. Computed tomography (CT) of head revealed venous infarct in left temporo-occipito-parietal region with linear area of hemorrhage within it with large left fronto-temporo-parietal acute subdural hematoma with midline shift of 9 mm toward right side with subfalcine herniation with descending transtentorial herniation with sub-arachnoid hemorrhage in the left parietal and occipital sulci with diffuse cerebral edema [].\nCT venography revealed thrombosis in superior sagittal sinus extending to adjacent cortical veins []. She was immediately taken for surgery, and a left fronto-temporo-parietal decompressive craniectomy was performed with the evacuation of acute subdural hematoma and lax duroplasty. However, she continued to deteriorate in the postoperative period and died on the first postoperative day.

Write a detailed clinical case vignette based on the following key phrases: Subdural Hematoma, Cerebral Venous Thrombosis, Dural Arteriovenous Fistula

A 66-year-old male with a recent syncope-related fall and closed head injury presented with progressively worsening gait instability, dizziness, and headaches. The fall occurred 1 week before presentation. On examination, no focal neurologic deficits were found. Noncontrast head CT demonstrated a 7 mm right convexity mixed density subdural hematoma [ and ]. Given his significant headaches and progressive functional decline, MMA embolization was performed as primary treatment. Intraprocedural digital subtraction angiogram revealed a right parietal Cognard Grade I DAVF [ and ]. Given the absence of cortical venous reflux and benign natural history of the fistula, the remainder of the procedure did not deviate from routine MMA embolization. The right temporal and right frontoparietal branches of the MMA were embolized with n-BCA glue with indirect penetration of liquid embolic into the fistulous point. Following embolization, there was no further opacification of the fistula. The patient experienced no procedure-related complication and was discharged the subsequent day. At 1-month follow-up, there was complete resolution of his presenting symptoms and surveillance CT demonstrated no residual SDH.

A 40-year-old female presented to an emergency in altered sensorium with right hemiplegia with a history of a severe headache and multiple episodes of vomiting 1 day prior to admission. She was on oral contraceptives for last 2 years. Her Glasgow Coma Scale at admission was E1M3V1 and left pupil was dilated and not reacting to light. Computed tomography (CT) of head revealed venous infarct in left temporo-occipito-parietal region with linear area of hemorrhage within it with large left fronto-temporo-parietal acute subdural hematoma with midline shift of 9 mm toward right side with subfalcine herniation with descending transtentorial herniation with sub-arachnoid hemorrhage in the left parietal and occipital sulci with diffuse cerebral edema [].\nCT venography revealed thrombosis in superior sagittal sinus extending to adjacent cortical veins []. She was immediately taken for surgery, and a left fronto-temporo-parietal decompressive craniectomy was performed with the evacuation of acute subdural hematoma and lax duroplasty. However, she continued to deteriorate in the postoperative period and died on the first postoperative day.

Write a detailed clinical case vignette based on the following key phrases: Subdural Hematoma, Cerebral Venous Thrombosis, Dural Arteriovenous Fistula

A 58-year-old right-handed postmenopausal woman presented to the emergency with progressively increasing holocephalic headache for 3 days. She did not have fever, nausea, and vomiting. The headache gradually worsened in severity and on the day of presentation, she developed a generalized tonic clonic seizure. Apart from the history of well-controlled diabetes mellitus, she did not have significant past medical, personal, and family history. She had not received any vaccines in the recent past. On examination, she was ill-looking, but her vital signs were stable. She had Wernicke's aphasia. She did not have disc edema; cranial nerve examination was normal, and she did not have any focal deficits.\nAn urgent CT scan of the head without contrast showed left temporal hematoma with surrounding vasogenic edema (Figure ). Hemorrhagic picture was noted in the insular cistern (Figure ), left fronto-temporal subdural space (Figure ), the perimesencephalic, ambient and suprasellar cisterns (Figures and ), and the sulci of the left temporo-parietal lobes (Figures and ). There was a subtle dense clot sign in the left transverse sinus (Figure ). She was diagnosed as having left transverse sinus thrombosis leading to left temporal hematoma, SAH and SDH. She was treated with low molecular weight heparin, levetiracetam, and 3% hypertonic saline. The magnetic resonance venography (MRV) done the following day confirmed the presence of left transverse sinus thrombosis (Figure ). CT angiography of the brain did not reveal any vascular malformations. Her complete blood counts, coagulation profiles, routine blood chemistry, and C-reactive protein were within normal limits. Antinuclear antibody and SARS-CoV-2 RNA polymerase chain reaction tests were negative. She underwent CT scan of neck, chest, abdomen and pelvis, mammogram, stool occult blood, carcinoembryonic antigen, CA-125, and Ca 19–9 tests, all of which were non-contributory to any occult malignancy. Thrombophilia screening was not done at this acute stage. We decided to get those done after the completion of anticoagulant treatment. She showed good clinical improvement over the course of the next few days. A repeat CT scan of the head done on day seven, revealed decreasing edema and stable hematoma volume with no new bleeding. The cause of her CVST was deemed undermined at this stage and she was discharged home on dabigatran 150 mg twice daily, as she could not get PT/INR done reliably due to the current lockdown imposed by the government. She has been doing well on follow up.

A 40-year-old female presented to an emergency in altered sensorium with right hemiplegia with a history of a severe headache and multiple episodes of vomiting 1 day prior to admission. She was on oral contraceptives for last 2 years. Her Glasgow Coma Scale at admission was E1M3V1 and left pupil was dilated and not reacting to light. Computed tomography (CT) of head revealed venous infarct in left temporo-occipito-parietal region with linear area of hemorrhage within it with large left fronto-temporo-parietal acute subdural hematoma with midline shift of 9 mm toward right side with subfalcine herniation with descending transtentorial herniation with sub-arachnoid hemorrhage in the left parietal and occipital sulci with diffuse cerebral edema [].\nCT venography revealed thrombosis in superior sagittal sinus extending to adjacent cortical veins []. She was immediately taken for surgery, and a left fronto-temporo-parietal decompressive craniectomy was performed with the evacuation of acute subdural hematoma and lax duroplasty. However, she continued to deteriorate in the postoperative period and died on the first postoperative day.

Write a detailed clinical case vignette based on the following key phrases: Subdural Hematoma, Cerebral Venous Thrombosis, Dural Arteriovenous Fistula

A 77-year-old male with a recent syncope-related fall and closed head injury presented with gradually worsening isolated right upper extremity monoparesis. The fall occurred 1 month before presentation. On examination, the patient demonstrated 4/5 strength in his right upper extremity, with no additional neurologic deficits. Noncontrast head CT demonstrated bilateral mixed density convexity subdural hematomas [22 mm on the left and 14 mm on the right; and ]. The patient underwent a left craniotomy for evacuation of the larger hematoma, in conjunction with bilateral MMA embolization as primary treatment for the right convexity subdural hematoma in addition to limiting potential recurrence along the left convexity. Intraprocedural digital subtraction angiogram revealed two Cognard Grade III DAVFs, one arising from the parietal branch of the right MMA draining into an occipital cortical vein, and the second arising from the temporal branch of the left MMA draining into the vein of Labbe [-]. Given the presence of cortical venous reflux and associated risk of future intracranial hemorrhage, treatment of the fistulae was indicated. This was approached in two staged procedures. Following an uncomplicated left MMA embolization (frontoparietal branch), the incidental findings were discussed with the patient and he underwent a second stage embolization for the DAVF on a later date. During the second stage, a more prolonged infusion of liquid embolic was employed to ensure penetration into the recipient cortical venous outflow, resulting in nonopacification of the aforementioned fistulae. The postoperative course was complicated by seizures which resolved with uptitration in antiepileptic medications. At 6-month follow-up, there was complete resolution of the patient’s presenting symptoms and surveillance CT demonstrated no residual SDH.

A 40-year-old female presented to an emergency in altered sensorium with right hemiplegia with a history of a severe headache and multiple episodes of vomiting 1 day prior to admission. She was on oral contraceptives for last 2 years. Her Glasgow Coma Scale at admission was E1M3V1 and left pupil was dilated and not reacting to light. Computed tomography (CT) of head revealed venous infarct in left temporo-occipito-parietal region with linear area of hemorrhage within it with large left fronto-temporo-parietal acute subdural hematoma with midline shift of 9 mm toward right side with subfalcine herniation with descending transtentorial herniation with sub-arachnoid hemorrhage in the left parietal and occipital sulci with diffuse cerebral edema [].\nCT venography revealed thrombosis in superior sagittal sinus extending to adjacent cortical veins []. She was immediately taken for surgery, and a left fronto-temporo-parietal decompressive craniectomy was performed with the evacuation of acute subdural hematoma and lax duroplasty. However, she continued to deteriorate in the postoperative period and died on the first postoperative day.

Write a detailed clinical case vignette based on the following key phrases: Subdural Hematoma, Cerebral Venous Thrombosis, Dural Arteriovenous Fistula

A 60-year-old male experienced one month of escalating bifrontal headaches refractory to analgesics and antibiotics prescribed for presumed sinusitis. The headaches increased during sneezing, bending over, or bedrest and improved when he was sitting or standing. There was no history of trauma. His prior medical history was notable for hypertension and hyperlipidemia. There was no family history of coagulopathy or thrombophilia. He was married, employed, used 0.5 packs of tobacco (7.5 packs/years), consumed alcohol socially, and did not use any illicit drugs. His vital signs were notable for sinus bradycardia with a heart rate of 39 and elevated BP of 184/86 mmHg. He had no other significant findings on physical examination; detailed neurologic examination was unremarkable. Routine admission laboratory studies were within normal limits. Coagulation studies including platelet function assays were normal.\nNoncontrasted head CT demonstrated a 19 mm left isodense SDH with 10 mm of midline shift []. The collection was more prominent in the frontal region. A CT angiogram was obtained prior to surgery, and no source of bleeding was identified. He underwent a mini-craniotomy; and repeat CT imaging after the procedure [] demonstrated excellent hematoma evacuation and brain reexpansion.\nA scheduled follow up head CT obtained on postoperative day 27 was notable for recurrent SDH with a frontal predilection \n[]. The appearance and location were similar to the initial presentation. He was readmitted to the hospital and underwent SDH drainage via burr hole. On subsequent imaging with MRI, MR angiography, and MR venography, a filling defect was visible in the distal left transverse sinus and no flow was observed in the distal left sigmoid sinus or internal jugular vein. These findings were confirmed on CT venography.\nPatient underwent cerebral angiography on postoperative day 7 after SDH evacuation []. Left carotid injection was notable for a prominent left vein of Labbe with delayed wash-out, a filling defect in the left transverse sinus, and retrograde flow in the left transverse sinus with subsequent drainage into the right transverse sinus. Transvenous catheterization confirmed retrograde drainage of the left transverse sinus and venous stasis in the left vein of Labbe. Manometric readings in the left sigmoid sinus and both transverse sinuses were elevated (18-25 mmHg range). Thrombectomy with the Penumbra device and venoplasty with 7 × 20 mm balloon were performed; 10 mg of systemic abciximab was administered. Follow up venography demonstrated improved flow in the left vein of Labbe, restored normal direction of flow in the sinuses with normalized pressure (11 mmHg) in the left transverse sinus. Daily aspirin (325 mg) was initiated on the day of this intervention; patient was discharged home without neurologic deficits. A follow-up CT venogram at 6 weeks demonstrated patent venous sinuses and no recurrence of his SDH. His 3 month clinical outcome was excellent (modified Rankin score 0).

A 40-year-old female presented to an emergency in altered sensorium with right hemiplegia with a history of a severe headache and multiple episodes of vomiting 1 day prior to admission. She was on oral contraceptives for last 2 years. Her Glasgow Coma Scale at admission was E1M3V1 and left pupil was dilated and not reacting to light. Computed tomography (CT) of head revealed venous infarct in left temporo-occipito-parietal region with linear area of hemorrhage within it with large left fronto-temporo-parietal acute subdural hematoma with midline shift of 9 mm toward right side with subfalcine herniation with descending transtentorial herniation with sub-arachnoid hemorrhage in the left parietal and occipital sulci with diffuse cerebral edema [].\nCT venography revealed thrombosis in superior sagittal sinus extending to adjacent cortical veins []. She was immediately taken for surgery, and a left fronto-temporo-parietal decompressive craniectomy was performed with the evacuation of acute subdural hematoma and lax duroplasty. However, she continued to deteriorate in the postoperative period and died on the first postoperative day.

Write a detailed clinical case vignette based on the following key phrases: Subdural Hematoma, Cerebral Venous Thrombosis, Dural Arteriovenous Fistula

A 59-year-old male with a recent fall and closed head injury presented with progressively worsening headaches. The fall occurred 9 days before presentation. On examination, no neurologic deficits were found. Noncontrast head CT demonstrated a 5 mm left convexity CSDH []. He underwent burr hole evacuation and was discharged on the subsequent day. He presented again on postoperative day 6 with recurrence of his headaches. Noncontrast head CT demonstrated recurrence of the left convexity subdural hematoma []. He subsequently underwent a left craniotomy for evacuation. He was discharged on postoperative day 2 with no postprocedural complications. At 1-month follow-up, he continued to complain of severe headaches. Surveillance CT demonstrated a new 27 mm right convexity mixed density subdural hematoma [ and ]. He subsequently underwent right MMA embolization as primary treatment. Intraprocedural digital subtraction angiogram revealed a Cognard Grade III cribriform plate DAVF supplied by the right ophthalmic artery draining into a right frontal cortical vein [ and ]. The right MMA temporoparietal and frontal branches were embolized with n-BCA glue. Follow-up was arranged to treat the DAVF at a later date and he was discharged the following day. The patient was subsequently lost to follow-up, but presented to the emergency department 4 months later with diplopia and a right abducens nerve palsy. Noncontrast head CT demonstrated significant reduction in size of the previously embolized right convexity subdural hematoma. He was admitted and underwent attempted endovascular treatment of the DAVF. Catheterization of the arterial and venous sides of the fistula achieved suboptimal positioning for liquid embolic embolization and so he underwent a right craniotomy for surgical ligation of the fistula. The patient experienced no postprocedural complications. At 2-week follow-up, there was complete resolution of his presenting symptoms and surveillance CT demonstrated no residual SDH.

A 40-year-old female presented to an emergency in altered sensorium with right hemiplegia with a history of a severe headache and multiple episodes of vomiting 1 day prior to admission. She was on oral contraceptives for last 2 years. Her Glasgow Coma Scale at admission was E1M3V1 and left pupil was dilated and not reacting to light. Computed tomography (CT) of head revealed venous infarct in left temporo-occipito-parietal region with linear area of hemorrhage within it with large left fronto-temporo-parietal acute subdural hematoma with midline shift of 9 mm toward right side with subfalcine herniation with descending transtentorial herniation with sub-arachnoid hemorrhage in the left parietal and occipital sulci with diffuse cerebral edema [].\nCT venography revealed thrombosis in superior sagittal sinus extending to adjacent cortical veins []. She was immediately taken for surgery, and a left fronto-temporo-parietal decompressive craniectomy was performed with the evacuation of acute subdural hematoma and lax duroplasty. However, she continued to deteriorate in the postoperative period and died on the first postoperative day.

Write a detailed clinical case vignette based on the following key phrases: Subdural Hematoma, Cerebral Venous Thrombosis, Dural Arteriovenous Fistula

A 68-year-old woman with polycythemia vera experienced a global, nonpositional headache for one day. She subsequently became comatose. On emergent evaluation she exhibited decorticate posturing. Her Glasgow coma score was 6. There was no preceding history of trauma, infection, or dehydration. She was not on anticoagulants or antiplatelet agents. Her polycythemia vera had been managed with therapeutic phlebotomy and hydroxyurea (500 mg daily). She had no prior history of thromboembolic events. Noncontrasted head CT showed extensive left 20 mm acute SDH with 16 mm of midline shift []. She underwent emergent craniotomy and hematoma evacuation. On careful inspection of the exposed brain, a prominent and engorged cortical vein observed. No other vascular abnormalities or potential bleeding sources were identified. CT venography and MR venography detected partial superior sagittal sinus thrombosis, which leads to the empty delta sign (the intraluminal thrombus prevents central filling of the sinus; ). She was managed conservatively with hydroxyurea, hydration, and aspirin. Laboratory analyses were notable for normal coagulation panel, normal platelet function assays, hematocrit of 45.9, negative thrombophilia evaluation (protein S, protein C, antithrombin III, anticardiolipin antibody, homocysteine, lupus anticoagulant, beta-2 glycoprotein antibodies, Factor V Leiden mutation, prothrombin gene mutation). Analysis of DNA extracted from her blood revealed the presence of the V617F mutation within the JAK2 gene. Her 3-month outcome was poor (modified Rankin score 4).

A 40-year-old female presented to an emergency in altered sensorium with right hemiplegia with a history of a severe headache and multiple episodes of vomiting 1 day prior to admission. She was on oral contraceptives for last 2 years. Her Glasgow Coma Scale at admission was E1M3V1 and left pupil was dilated and not reacting to light. Computed tomography (CT) of head revealed venous infarct in left temporo-occipito-parietal region with linear area of hemorrhage within it with large left fronto-temporo-parietal acute subdural hematoma with midline shift of 9 mm toward right side with subfalcine herniation with descending transtentorial herniation with sub-arachnoid hemorrhage in the left parietal and occipital sulci with diffuse cerebral edema [].\nCT venography revealed thrombosis in superior sagittal sinus extending to adjacent cortical veins []. She was immediately taken for surgery, and a left fronto-temporo-parietal decompressive craniectomy was performed with the evacuation of acute subdural hematoma and lax duroplasty. However, she continued to deteriorate in the postoperative period and died on the first postoperative day.

Write a detailed clinical case vignette based on the following key phrases: Subdural Hematoma, Cerebral Venous Thrombosis, Dural Arteriovenous Fistula

A 59-year-old male patient suffered from rapidly progressive and pulsatile headache over the right parietal region characterized as thunderclap and nausea. He had no fever. These symptoms were followed by generalized seizure. Neurological examination showed a normal level of consciousness. On examination, meningism was seen. The rest of the physical examination was unremarkable. CT scan head was normal. MRI revealed right parasagittal high fronto-parietal subarachnoid hemorrhage with mild gyral edema. MRV showed superior sagittal sinus and bilateral transverse sinus thrombosis [Figures and ]. DSA confirmed [Figures and ] the diagnosis of DST without any potential cause of SAH. Coagulation testing, including prothrombin time, activated prothrombin time, anticardiolipin antibody titer, antiphospholipid antibody titer, homocysteine titer, and levels of protein C and S, antithrombin III, and fibrinogen were all within normal limits and done simultaneously with MRI, MR Venography, DSA within one to two days of admission. Subcutaneous LMW heparin therapy was given. The patient's condition stabilized after nine days of treatment. Oral warfarin maintained an INR of 2.0-3.0. Patient's improvement was clinically satisfactory within six weeks, Repeat DSA done after six weeks was normal, except minimal filling defect. Patient was followed up at two-weeks intervals for three months

A 40-year-old female presented to an emergency in altered sensorium with right hemiplegia with a history of a severe headache and multiple episodes of vomiting 1 day prior to admission. She was on oral contraceptives for last 2 years. Her Glasgow Coma Scale at admission was E1M3V1 and left pupil was dilated and not reacting to light. Computed tomography (CT) of head revealed venous infarct in left temporo-occipito-parietal region with linear area of hemorrhage within it with large left fronto-temporo-parietal acute subdural hematoma with midline shift of 9 mm toward right side with subfalcine herniation with descending transtentorial herniation with sub-arachnoid hemorrhage in the left parietal and occipital sulci with diffuse cerebral edema [].\nCT venography revealed thrombosis in superior sagittal sinus extending to adjacent cortical veins []. She was immediately taken for surgery, and a left fronto-temporo-parietal decompressive craniectomy was performed with the evacuation of acute subdural hematoma and lax duroplasty. However, she continued to deteriorate in the postoperative period and died on the first postoperative day.

Write a detailed clinical case vignette based on the following key phrases: Subdural Hematoma, Cerebral Venous Thrombosis, Dural Arteriovenous Fistula

A 25-year-old primigravida with a history of pre-eclampsia was brought to the emergency department with sudden onset of severe headache. The headache started two days after delivery. It was followed by confusion and loss of consciousness over a few hours. On initial evaluation, the patient was confused with a Glasgow Coma Scale (GCS) of 12/15, blood pressure of 130/90 mmHg, pulse rate of 82 beats/min, respiratory rate of 30/min, temperature 98°C, and oxygen saturation of 97 mmHg at room temperature. On physical examination, bilateral equivocal planters were noted with no other significant findings, and bilateral papillary edema on fundoscopy was seen. The rest of the review system was unremarkable. She underwent an urgent MRI with magnetic resonance venography (MRV) of the brain, which showed right transverse sinus thrombosis with an element of SAH (Figure ).\nCoagulation profile, including thrombin time (TT), prothrombin time (PT), partial thromboplastin time (PTT), antithrombin III, fibrinogen, proteins C and S, antiphospholipid antibody titers, and homocysteine levels, were normal. She was started on a half dosage of low molecular weight heparin (LMWH) (60 mg subcutaneously once a day) with regular monitoring of her blood pressure and GCS. Her GCS started improving; therefore, she was continued on a half dose of LMWH for 10 days, and brain MRI was repeated after 10 days, which showed the gradual resolution of SAH (Figure ). The quantity of LMWH was doubled, and warfarin was started after a full dose of LMWH. After improving her GCS and achievement of international normalized ratio (INR) of two to three, she was discharged with the advice of regular INR monitoring and follow-up to the outpatient department. On follow-up at six weeks, MRI with MRV was repeated, which showed thrombosis had resolved, although a mild filling defect was noted. She was kept on anticoagulants for one year, and on further follow-up at six months, she was doing well.

This 67-year-old male man has had a progressively worsening pain on the left cranium over 2 weeks that intractable to some analgesics. There was no recent head trauma or other medical disease in his history. On admission, the general physical and neurologic investigations were not remarkable. Routine laboratory evaluations including coagulation profiles and platelet function were within normal limits.\nBrain computed tomography (CT) scans revealed an isodense left-sided CSDH with marked cerebral shifting (). There was no evidence of source of this hemorrhage with temporal predilection on the CT angiogram. On magnetic resonance (MR) image subsequently obtained, the abnormal intensity within the subarachnoid space and the brain parenchyma was not visible. The patency without steno-occlusion in both transverse and sigmoid sinuses was clearly delineated on T2-weighted sequences (). This patient has received a trephination and SDH drainage, after that he was sent home with resolution of headache. Approximately 2 weeks later, however, he developed an excruciating pain in the temporal and parietal regions with recurrence of subdural collection. The site and density of hematoma was similar to the first presentation (). He was immediately returned for subdural irrigation and decompression through the prior burr-holes. The patient's clinical course was not eventful, but he complained of a mild headache again. Follow-up CT scanned just prior to discharge was strikingly for the newly-formed thin hematoma at the operative site (). Another evacuation of this subacute subdural clot was not deemed to be necessary.\nAt this time, an active intervention was sought for this patient who had an intractably recurring CSDH. On the 7th day after the second surgery, angiography was performed to rule out an occult vascular lesion. A flow-guided type microcatheter (Prowler 10™, Cordis Neurovascular, Miami Lakes, FL, USA) was positioned in the main trunk of the MMA for selective angiography. The frontal and parietal branch of the MMA was appeared normally, and the abnormal membrane staining on the affected side was not detected. A left external carotid angiogram disclosed a dural AVF between the petrosquamosal branch of the MMA and the transverse-sigmoid sinus without retrograde cortical venous draining. The AV shunt had no connection to the internal carotid artery and its branches. It was suggested that the bleeding from the draining venous system of the dural AVF led to refractory CSDH. The microcatheter was introduced into the petrosquamosal branch of the MMA, thereafter polyvinyl alcohol particles ranging 150 to 250 µm were distally injected (). After trans-arterial obliteration of the feeder and fistula, the AV shunt disappeared. The recurrent hematoma of this patient did not increase, and his complaints of headache gradually subsided. The brain CT at one year following the embolization therapy revealed complete regression of the subdural hematomas ().

Write a detailed clinical case vignette based on the following key phrases: Subdural Hematoma, Cerebral Venous Thrombosis, Dural Arteriovenous Fistula

A 25-year-old primigravida with a history of pre-eclampsia was brought to the emergency department with sudden onset of severe headache. The headache started two days after delivery. It was followed by confusion and loss of consciousness over a few hours. On initial evaluation, the patient was confused with a Glasgow Coma Scale (GCS) of 12/15, blood pressure of 130/90 mmHg, pulse rate of 82 beats/min, respiratory rate of 30/min, temperature 98°C, and oxygen saturation of 97 mmHg at room temperature. On physical examination, bilateral equivocal planters were noted with no other significant findings, and bilateral papillary edema on fundoscopy was seen. The rest of the review system was unremarkable. She underwent an urgent MRI with magnetic resonance venography (MRV) of the brain, which showed right transverse sinus thrombosis with an element of SAH (Figure ).\nCoagulation profile, including thrombin time (TT), prothrombin time (PT), partial thromboplastin time (PTT), antithrombin III, fibrinogen, proteins C and S, antiphospholipid antibody titers, and homocysteine levels, were normal. She was started on a half dosage of low molecular weight heparin (LMWH) (60 mg subcutaneously once a day) with regular monitoring of her blood pressure and GCS. Her GCS started improving; therefore, she was continued on a half dose of LMWH for 10 days, and brain MRI was repeated after 10 days, which showed the gradual resolution of SAH (Figure ). The quantity of LMWH was doubled, and warfarin was started after a full dose of LMWH. After improving her GCS and achievement of international normalized ratio (INR) of two to three, she was discharged with the advice of regular INR monitoring and follow-up to the outpatient department. On follow-up at six weeks, MRI with MRV was repeated, which showed thrombosis had resolved, although a mild filling defect was noted. She was kept on anticoagulants for one year, and on further follow-up at six months, she was doing well.

A 66-year-old male with a recent syncope-related fall and closed head injury presented with progressively worsening gait instability, dizziness, and headaches. The fall occurred 1 week before presentation. On examination, no focal neurologic deficits were found. Noncontrast head CT demonstrated a 7 mm right convexity mixed density subdural hematoma [ and ]. Given his significant headaches and progressive functional decline, MMA embolization was performed as primary treatment. Intraprocedural digital subtraction angiogram revealed a right parietal Cognard Grade I DAVF [ and ]. Given the absence of cortical venous reflux and benign natural history of the fistula, the remainder of the procedure did not deviate from routine MMA embolization. The right temporal and right frontoparietal branches of the MMA were embolized with n-BCA glue with indirect penetration of liquid embolic into the fistulous point. Following embolization, there was no further opacification of the fistula. The patient experienced no procedure-related complication and was discharged the subsequent day. At 1-month follow-up, there was complete resolution of his presenting symptoms and surveillance CT demonstrated no residual SDH.

Write a detailed clinical case vignette based on the following key phrases: Subdural Hematoma, Cerebral Venous Thrombosis, Dural Arteriovenous Fistula

A 25-year-old primigravida with a history of pre-eclampsia was brought to the emergency department with sudden onset of severe headache. The headache started two days after delivery. It was followed by confusion and loss of consciousness over a few hours. On initial evaluation, the patient was confused with a Glasgow Coma Scale (GCS) of 12/15, blood pressure of 130/90 mmHg, pulse rate of 82 beats/min, respiratory rate of 30/min, temperature 98°C, and oxygen saturation of 97 mmHg at room temperature. On physical examination, bilateral equivocal planters were noted with no other significant findings, and bilateral papillary edema on fundoscopy was seen. The rest of the review system was unremarkable. She underwent an urgent MRI with magnetic resonance venography (MRV) of the brain, which showed right transverse sinus thrombosis with an element of SAH (Figure ).\nCoagulation profile, including thrombin time (TT), prothrombin time (PT), partial thromboplastin time (PTT), antithrombin III, fibrinogen, proteins C and S, antiphospholipid antibody titers, and homocysteine levels, were normal. She was started on a half dosage of low molecular weight heparin (LMWH) (60 mg subcutaneously once a day) with regular monitoring of her blood pressure and GCS. Her GCS started improving; therefore, she was continued on a half dose of LMWH for 10 days, and brain MRI was repeated after 10 days, which showed the gradual resolution of SAH (Figure ). The quantity of LMWH was doubled, and warfarin was started after a full dose of LMWH. After improving her GCS and achievement of international normalized ratio (INR) of two to three, she was discharged with the advice of regular INR monitoring and follow-up to the outpatient department. On follow-up at six weeks, MRI with MRV was repeated, which showed thrombosis had resolved, although a mild filling defect was noted. She was kept on anticoagulants for one year, and on further follow-up at six months, she was doing well.

A 58-year-old right-handed postmenopausal woman presented to the emergency with progressively increasing holocephalic headache for 3 days. She did not have fever, nausea, and vomiting. The headache gradually worsened in severity and on the day of presentation, she developed a generalized tonic clonic seizure. Apart from the history of well-controlled diabetes mellitus, she did not have significant past medical, personal, and family history. She had not received any vaccines in the recent past. On examination, she was ill-looking, but her vital signs were stable. She had Wernicke's aphasia. She did not have disc edema; cranial nerve examination was normal, and she did not have any focal deficits.\nAn urgent CT scan of the head without contrast showed left temporal hematoma with surrounding vasogenic edema (Figure ). Hemorrhagic picture was noted in the insular cistern (Figure ), left fronto-temporal subdural space (Figure ), the perimesencephalic, ambient and suprasellar cisterns (Figures and ), and the sulci of the left temporo-parietal lobes (Figures and ). There was a subtle dense clot sign in the left transverse sinus (Figure ). She was diagnosed as having left transverse sinus thrombosis leading to left temporal hematoma, SAH and SDH. She was treated with low molecular weight heparin, levetiracetam, and 3% hypertonic saline. The magnetic resonance venography (MRV) done the following day confirmed the presence of left transverse sinus thrombosis (Figure ). CT angiography of the brain did not reveal any vascular malformations. Her complete blood counts, coagulation profiles, routine blood chemistry, and C-reactive protein were within normal limits. Antinuclear antibody and SARS-CoV-2 RNA polymerase chain reaction tests were negative. She underwent CT scan of neck, chest, abdomen and pelvis, mammogram, stool occult blood, carcinoembryonic antigen, CA-125, and Ca 19–9 tests, all of which were non-contributory to any occult malignancy. Thrombophilia screening was not done at this acute stage. We decided to get those done after the completion of anticoagulant treatment. She showed good clinical improvement over the course of the next few days. A repeat CT scan of the head done on day seven, revealed decreasing edema and stable hematoma volume with no new bleeding. The cause of her CVST was deemed undermined at this stage and she was discharged home on dabigatran 150 mg twice daily, as she could not get PT/INR done reliably due to the current lockdown imposed by the government. She has been doing well on follow up.

Write a detailed clinical case vignette based on the following key phrases: Subdural Hematoma, Cerebral Venous Thrombosis, Dural Arteriovenous Fistula

A 25-year-old primigravida with a history of pre-eclampsia was brought to the emergency department with sudden onset of severe headache. The headache started two days after delivery. It was followed by confusion and loss of consciousness over a few hours. On initial evaluation, the patient was confused with a Glasgow Coma Scale (GCS) of 12/15, blood pressure of 130/90 mmHg, pulse rate of 82 beats/min, respiratory rate of 30/min, temperature 98°C, and oxygen saturation of 97 mmHg at room temperature. On physical examination, bilateral equivocal planters were noted with no other significant findings, and bilateral papillary edema on fundoscopy was seen. The rest of the review system was unremarkable. She underwent an urgent MRI with magnetic resonance venography (MRV) of the brain, which showed right transverse sinus thrombosis with an element of SAH (Figure ).\nCoagulation profile, including thrombin time (TT), prothrombin time (PT), partial thromboplastin time (PTT), antithrombin III, fibrinogen, proteins C and S, antiphospholipid antibody titers, and homocysteine levels, were normal. She was started on a half dosage of low molecular weight heparin (LMWH) (60 mg subcutaneously once a day) with regular monitoring of her blood pressure and GCS. Her GCS started improving; therefore, she was continued on a half dose of LMWH for 10 days, and brain MRI was repeated after 10 days, which showed the gradual resolution of SAH (Figure ). The quantity of LMWH was doubled, and warfarin was started after a full dose of LMWH. After improving her GCS and achievement of international normalized ratio (INR) of two to three, she was discharged with the advice of regular INR monitoring and follow-up to the outpatient department. On follow-up at six weeks, MRI with MRV was repeated, which showed thrombosis had resolved, although a mild filling defect was noted. She was kept on anticoagulants for one year, and on further follow-up at six months, she was doing well.

A 77-year-old male with a recent syncope-related fall and closed head injury presented with gradually worsening isolated right upper extremity monoparesis. The fall occurred 1 month before presentation. On examination, the patient demonstrated 4/5 strength in his right upper extremity, with no additional neurologic deficits. Noncontrast head CT demonstrated bilateral mixed density convexity subdural hematomas [22 mm on the left and 14 mm on the right; and ]. The patient underwent a left craniotomy for evacuation of the larger hematoma, in conjunction with bilateral MMA embolization as primary treatment for the right convexity subdural hematoma in addition to limiting potential recurrence along the left convexity. Intraprocedural digital subtraction angiogram revealed two Cognard Grade III DAVFs, one arising from the parietal branch of the right MMA draining into an occipital cortical vein, and the second arising from the temporal branch of the left MMA draining into the vein of Labbe [-]. Given the presence of cortical venous reflux and associated risk of future intracranial hemorrhage, treatment of the fistulae was indicated. This was approached in two staged procedures. Following an uncomplicated left MMA embolization (frontoparietal branch), the incidental findings were discussed with the patient and he underwent a second stage embolization for the DAVF on a later date. During the second stage, a more prolonged infusion of liquid embolic was employed to ensure penetration into the recipient cortical venous outflow, resulting in nonopacification of the aforementioned fistulae. The postoperative course was complicated by seizures which resolved with uptitration in antiepileptic medications. At 6-month follow-up, there was complete resolution of the patient’s presenting symptoms and surveillance CT demonstrated no residual SDH.

Write a detailed clinical case vignette based on the following key phrases: Subdural Hematoma, Cerebral Venous Thrombosis, Dural Arteriovenous Fistula

A 25-year-old primigravida with a history of pre-eclampsia was brought to the emergency department with sudden onset of severe headache. The headache started two days after delivery. It was followed by confusion and loss of consciousness over a few hours. On initial evaluation, the patient was confused with a Glasgow Coma Scale (GCS) of 12/15, blood pressure of 130/90 mmHg, pulse rate of 82 beats/min, respiratory rate of 30/min, temperature 98°C, and oxygen saturation of 97 mmHg at room temperature. On physical examination, bilateral equivocal planters were noted with no other significant findings, and bilateral papillary edema on fundoscopy was seen. The rest of the review system was unremarkable. She underwent an urgent MRI with magnetic resonance venography (MRV) of the brain, which showed right transverse sinus thrombosis with an element of SAH (Figure ).\nCoagulation profile, including thrombin time (TT), prothrombin time (PT), partial thromboplastin time (PTT), antithrombin III, fibrinogen, proteins C and S, antiphospholipid antibody titers, and homocysteine levels, were normal. She was started on a half dosage of low molecular weight heparin (LMWH) (60 mg subcutaneously once a day) with regular monitoring of her blood pressure and GCS. Her GCS started improving; therefore, she was continued on a half dose of LMWH for 10 days, and brain MRI was repeated after 10 days, which showed the gradual resolution of SAH (Figure ). The quantity of LMWH was doubled, and warfarin was started after a full dose of LMWH. After improving her GCS and achievement of international normalized ratio (INR) of two to three, she was discharged with the advice of regular INR monitoring and follow-up to the outpatient department. On follow-up at six weeks, MRI with MRV was repeated, which showed thrombosis had resolved, although a mild filling defect was noted. She was kept on anticoagulants for one year, and on further follow-up at six months, she was doing well.

A 60-year-old male experienced one month of escalating bifrontal headaches refractory to analgesics and antibiotics prescribed for presumed sinusitis. The headaches increased during sneezing, bending over, or bedrest and improved when he was sitting or standing. There was no history of trauma. His prior medical history was notable for hypertension and hyperlipidemia. There was no family history of coagulopathy or thrombophilia. He was married, employed, used 0.5 packs of tobacco (7.5 packs/years), consumed alcohol socially, and did not use any illicit drugs. His vital signs were notable for sinus bradycardia with a heart rate of 39 and elevated BP of 184/86 mmHg. He had no other significant findings on physical examination; detailed neurologic examination was unremarkable. Routine admission laboratory studies were within normal limits. Coagulation studies including platelet function assays were normal.\nNoncontrasted head CT demonstrated a 19 mm left isodense SDH with 10 mm of midline shift []. The collection was more prominent in the frontal region. A CT angiogram was obtained prior to surgery, and no source of bleeding was identified. He underwent a mini-craniotomy; and repeat CT imaging after the procedure [] demonstrated excellent hematoma evacuation and brain reexpansion.\nA scheduled follow up head CT obtained on postoperative day 27 was notable for recurrent SDH with a frontal predilection \n[]. The appearance and location were similar to the initial presentation. He was readmitted to the hospital and underwent SDH drainage via burr hole. On subsequent imaging with MRI, MR angiography, and MR venography, a filling defect was visible in the distal left transverse sinus and no flow was observed in the distal left sigmoid sinus or internal jugular vein. These findings were confirmed on CT venography.\nPatient underwent cerebral angiography on postoperative day 7 after SDH evacuation []. Left carotid injection was notable for a prominent left vein of Labbe with delayed wash-out, a filling defect in the left transverse sinus, and retrograde flow in the left transverse sinus with subsequent drainage into the right transverse sinus. Transvenous catheterization confirmed retrograde drainage of the left transverse sinus and venous stasis in the left vein of Labbe. Manometric readings in the left sigmoid sinus and both transverse sinuses were elevated (18-25 mmHg range). Thrombectomy with the Penumbra device and venoplasty with 7 × 20 mm balloon were performed; 10 mg of systemic abciximab was administered. Follow up venography demonstrated improved flow in the left vein of Labbe, restored normal direction of flow in the sinuses with normalized pressure (11 mmHg) in the left transverse sinus. Daily aspirin (325 mg) was initiated on the day of this intervention; patient was discharged home without neurologic deficits. A follow-up CT venogram at 6 weeks demonstrated patent venous sinuses and no recurrence of his SDH. His 3 month clinical outcome was excellent (modified Rankin score 0).

Write a detailed clinical case vignette based on the following key phrases: Subdural Hematoma, Cerebral Venous Thrombosis, Dural Arteriovenous Fistula

A 25-year-old primigravida with a history of pre-eclampsia was brought to the emergency department with sudden onset of severe headache. The headache started two days after delivery. It was followed by confusion and loss of consciousness over a few hours. On initial evaluation, the patient was confused with a Glasgow Coma Scale (GCS) of 12/15, blood pressure of 130/90 mmHg, pulse rate of 82 beats/min, respiratory rate of 30/min, temperature 98°C, and oxygen saturation of 97 mmHg at room temperature. On physical examination, bilateral equivocal planters were noted with no other significant findings, and bilateral papillary edema on fundoscopy was seen. The rest of the review system was unremarkable. She underwent an urgent MRI with magnetic resonance venography (MRV) of the brain, which showed right transverse sinus thrombosis with an element of SAH (Figure ).\nCoagulation profile, including thrombin time (TT), prothrombin time (PT), partial thromboplastin time (PTT), antithrombin III, fibrinogen, proteins C and S, antiphospholipid antibody titers, and homocysteine levels, were normal. She was started on a half dosage of low molecular weight heparin (LMWH) (60 mg subcutaneously once a day) with regular monitoring of her blood pressure and GCS. Her GCS started improving; therefore, she was continued on a half dose of LMWH for 10 days, and brain MRI was repeated after 10 days, which showed the gradual resolution of SAH (Figure ). The quantity of LMWH was doubled, and warfarin was started after a full dose of LMWH. After improving her GCS and achievement of international normalized ratio (INR) of two to three, she was discharged with the advice of regular INR monitoring and follow-up to the outpatient department. On follow-up at six weeks, MRI with MRV was repeated, which showed thrombosis had resolved, although a mild filling defect was noted. She was kept on anticoagulants for one year, and on further follow-up at six months, she was doing well.

A 59-year-old male with a recent fall and closed head injury presented with progressively worsening headaches. The fall occurred 9 days before presentation. On examination, no neurologic deficits were found. Noncontrast head CT demonstrated a 5 mm left convexity CSDH []. He underwent burr hole evacuation and was discharged on the subsequent day. He presented again on postoperative day 6 with recurrence of his headaches. Noncontrast head CT demonstrated recurrence of the left convexity subdural hematoma []. He subsequently underwent a left craniotomy for evacuation. He was discharged on postoperative day 2 with no postprocedural complications. At 1-month follow-up, he continued to complain of severe headaches. Surveillance CT demonstrated a new 27 mm right convexity mixed density subdural hematoma [ and ]. He subsequently underwent right MMA embolization as primary treatment. Intraprocedural digital subtraction angiogram revealed a Cognard Grade III cribriform plate DAVF supplied by the right ophthalmic artery draining into a right frontal cortical vein [ and ]. The right MMA temporoparietal and frontal branches were embolized with n-BCA glue. Follow-up was arranged to treat the DAVF at a later date and he was discharged the following day. The patient was subsequently lost to follow-up, but presented to the emergency department 4 months later with diplopia and a right abducens nerve palsy. Noncontrast head CT demonstrated significant reduction in size of the previously embolized right convexity subdural hematoma. He was admitted and underwent attempted endovascular treatment of the DAVF. Catheterization of the arterial and venous sides of the fistula achieved suboptimal positioning for liquid embolic embolization and so he underwent a right craniotomy for surgical ligation of the fistula. The patient experienced no postprocedural complications. At 2-week follow-up, there was complete resolution of his presenting symptoms and surveillance CT demonstrated no residual SDH.

Write a detailed clinical case vignette based on the following key phrases: Subdural Hematoma, Cerebral Venous Thrombosis, Dural Arteriovenous Fistula